3-alkyl-4-amido-bicyclic [4,5,0] hydroxamic acids as HDAC inhibitors

ABSTRACT

The present disclosure relates to inhibitors of zinc-dependent histone deacetylases (HDACs) useful in the treatment of diseases or disorders associated with an HDAC, e.g., HDAC6, having a Formula I: 
                         
where R, L, X 1 , X 2 , X 3 , X 4 , Y 1 , Y 2 , Y 3 , and Y 4  are described herein.

CROSS-REFERENCE TO RELATED APPLICATIONS

This application is a divisional of U.S. application Ser. No.16/567,007, filed Sep. 11, 2019, which is a divisional of U.S.application Ser. No. 16/219,648, filed Dec. 13, 2018, which is adivisional of U.S. application Ser. No. 15/013,814, filed Feb. 2, 2016,which claims the benefit of priority of U.S. Provisional Application No.62/110,716, filed Feb. 2, 2015 and U.S. Provisional Application No.62/205,438, filed Aug. 14, 2015, both all of which are incorporatedherein by reference in their entirety.

FIELD OF THE DISCLOSURE

The present disclosure relates to inhibitors of zinc-dependent histonedeacetylases (HDACs) useful in the treatment of diseases or disordersassociated with HDACs including cell proliferation diseases (e.g.,cancer), neurological and inflammatory diseases. Specifically, thisdisclosure is concerned with compounds and compositions inhibitingHDACs, methods of treating diseases associated with HDACs, and methodsof synthesizing these compounds.

BACKGROUND OF THE DISCLOSURE

Many members of the HDAC family require zinc (Zn) to function properly.For instance, the isozyme histone deacetylase 6 (HDAC6) is azinc-dependent histone deacetylase that possesses histone deacetylaseactivity. Other family members include HDACs 1-5 and 7-11. (De Ruijteret al, Biochem. J. 2003. 370; 737-749).

HDAC6 is known to deacetylate and associate with α-tubulin, cortactin,heat shock protein 90, ß-catenin, glucose-regulated protein 78 kDa,myosin heavy chain 9, heat shock cognate protein 70, and dnaJ homologsubfamily A member 1 (reviewed in Li et al, FEBS J. 2013, 280: 775-93;Zhang et al, Protein Cell. 2015, 6(1): 42-54). Diseases in which HDAC6inhibition could have a potential benefit include cancer (reviewed inAldana-Masangkay et al, J. Biomed. Biotechnol. 2011, 875824),specifically: multiple myeloma (Hideshima et al, Proc. Natl. Acad. Sci.USA 2005, 102(24):8567-8572); lung cancer (Kamemura et al, Biochem.Biophys. Res. Commun. 2008, 374(1):84-89); ovarian cancer (Bazzaro etal, Clin. Cancer Res. 2008, 14(22):7340-7347); breast cancer (Lee et al,Cancer Res. 2008, 68(18):7561-7569; Park et al, Oncol. Rep. 2011, 25:1677-81; Rey et al, Eur. J. Cell Biol. 2011, 90: 128-35); prostatecancer (Seidel et al, Biochem. Pharmacol. 2015 (15)00714-5); pancreaticcancer (Nawrocki et al, Cancer Res. 2006, 66(7):3773-3781); renal cancer(Cha et al, Clin. Cancer Res. 2009, 15(3): 840-850); hepatocellularcancer (Ding et al, FEBS Lett. 2013, 587:880-6; Kanno et al, Oncol. Rep.2012, 28: 867-73); lymphomas (Ding et al, Cancer Cell Int. 2014, 14:139;Amengual et al, Clin Cancer Res. 2015, 21(20):4663-75); and leukemiassuch as acute myeloid leukemia (AML) (Fiskus et al, Blood 2008,112(7):2896-2905) and acute lymphoblastic leukemia (ALL)(Rodriguez-Gonzalez et al, Blood 2008, 112(11): Abstract 1923)).

Inhibition of HDAC6 may also have a role in cardiovascular disease,including pressure overload, chronic ischemia, andinfarction-reperfusion injury (Tannous et al, Circulation 2008, 117(24):3070-3078); bacterial infection, including those caused byuropathogenic Escherichia coli (Dhakal and Mulve, J. Biol. Chem. 2008,284(1):446-454); neurological diseases caused by accumulation ofintracellular protein aggregates such as Alzheimer's, Parkinson's andHuntington's disease (reviewed in Simoes-Pires et al, Mol. Neurodegener.2013, 8: 7) or central nervous system trauma caused by tissue injury,oxidative-stress induced neuronal or axomal degeneration (Rivieccio etal, Proc. Natl. Acad. Sci. USA 2009, 106(46):19599-195604); andinflammation and autoimmune diseases through enhanced T cell-mediatedimmune tolerance at least in part through effects on regulatory T cells,including rheumatoid arthritis, psoriasis, spondylitis arthritis,psoriatic arthritis, multiple sclerosis, lupus, colitis and graft versushost disease (reviewed in Wang et al, Nat. Rev. Drug Disc. 20098(12):969-981; Vishwakarma et al, Int. Immunopharmacol. 2013, 16:72-8;Kalin et al, J. Med. Chem. 2012, 55:639-51); and fibrotic disease,including kidney fibrosis (Choi et al, Vascul. Pharmacol. 201572:130-140).

Four HDAC inhibitors are currently approved for the treatment of somecancers. These are suberanilohydroxamic acid (Vorinostat; Zolinza®) forthe treatment of cutaneous T cell lymphoma and multiple myeloma;Romidepsin (FK228; FR901228; Istodax®) for the treatment of peripheral Tcell lymphoma; Panobinostat (LBH-589; Farydak®) for the treatment ofmultiple myeloma; and belinostat (PXD101; Beleodaq®) for the treatmentof peripheral T cell lymphoma. However, these drugs are of limitedeffectiveness and can give rise to unwanted side effects. Thus there isa need for drugs with an improved safety-efficacy profile.

Given the complex function of HDAC6 and their potential utility in thetreatment of proliferative diseases, neurological diseases, andinflammatory diseases, there is a need for HDAC inhibitors (e.g., HDAC6inhibitors) with good therapeutic properties.

SUMMARY OF THE DISCLOSURE

One aspect of the disclosure relates to compounds of Formula I:

-   -   and pharmaceutically acceptable salts, prodrugs, solvates,        hydrates, tautomers and isomers thereof, wherein:    -   X¹ is independently CR¹R², NR³, O, or C═O;    -   X² and X⁴ are each independently CR¹R², C═O, S(O) or SO₂;    -   X³ is CR^(1′)R^(2′);    -   wherein X⁴, X², and X¹ are not all simultaneously CR¹R²;    -   Y¹ and Y⁴ are not bound to —C(O)NHOH and are each independently        N or CR¹;    -   Y² and Y³ are each independently N or CR¹ when not bonded to        —C(O)NHOH and Y² and Y³ are C when bonded to —C(O)NHOH;    -   L is —C(O)—, —C(O)(CR¹R²)_(m)—, or —C(O)(CR¹R²)_(m)O—, wherein L        is bound to the ring nitrogen through the carbonyl group;    -   R is independently —H, —C₁-C₆ alkyl, —C₂-C₆ alkenyl, —C₄-C₈        cycloalkenyl, —C₂-C₆ alkynyl, —C₃-C₈ cycloalkyl, —C₅-C₁₂        spirocycle, heterocyclyl, spiroheterocyclyl, aryl, or heteroaryl        containing 1-5 heteroatoms selected from the group consisting of        N, S, P, and O, wherein each alkyl, alkenyl, cycloalkenyl,        alkynyl, cycloalkyl, spirocycle, heterocyclyl,        spiroheterocyclyl, aryl, or heteroaryl is optionally substituted        with one or more —OH, halogen, oxo, —NO₂, —CN, —R¹, —R², —OR³,        —NHR³, —NR³R⁴, —S(O)₂NR³R⁴, —S(O)₂R¹, —C(O)R¹, or —CO₂R¹,        —NR³S(O)₂R¹, —S(O)R¹, —S(O)NR³R⁴, —NR³S(O)R¹, heterocycle, aryl,        or heteroaryl containing 1-5 heteroatoms selected from the group        consisting of N, S, P, and O, with the proviso that R is not        bound to L via a nitrogen atom;    -   R¹ and R² are independently, at each occurrence, —H, —R³, —R⁴,        —C₁-C₆ alkyl, —C₂-C₆ alkenyl, —C₃-C₈ cycloalkenyl, —C₂-C₆        alkynyl, —C₃-C₈ cycloalkyl, heterocyclyl, aryl, heteroaryl        containing 1-5 heteroatoms selected from the group consisting of        N, S, P, and O, —OH, halogen, —NO₂, —CN, —NHC₁-C₆ alkyl,        —N(C₁-C₆ alkyl)₂, —S(O)₂N(C₁-C₆ alkyl)₂, —N(C₁-C₆ alkyl)S(O)₂R⁵,        —S(O)₂(C₁-C₆ alkyl), —(C₁-C₆ alkyl)S(O)₂R⁵, —C(O)C₁-C₆ alkyl,        —CO₂C₁-C₆ alkyl, —N(C₁-C₆ alkyl)S(O)₂C₁-C₆ alkyl, or        (CHR⁵)_(n)NR³R⁴, wherein each alkyl, alkenyl, cycloalkenyl,        alkynyl, cycloalkyl, heterocyclyl, aryl, or heteroaryl is        optionally substituted with one or more substituents selected        from —OH, halogen, —NO₂, oxo, —CN, —R⁵, —OR³, —NHR³, NR³R⁴,        —S(O)₂N(R³)₂—, —S(O)₂R⁵, —C(O)R⁵, —CO₂R⁵, —NR³S(O)₂R⁵, —S(O)R⁵,        —S(O)NR³R⁴, —NR³S(O)R⁵, heterocycle, aryl, or heteroaryl        containing 1-5 heteroatoms selected from the group consisting of        N, S, P, and O;    -   or R¹ and R² can combine with the carbon atom to which they are        both attached to form a spirocycle, spiroheterocycle, or a        spirocycloalkenyl;    -   or R¹ and R², when on adjacent atoms, can combine to form a        heterocycle, cycloalkyl, aryl, heteroaryl containing 1-5        heteroatoms selected from the group consisting of N, S, P, and        O, or cycloalkenyl;    -   or R¹ and R², when on non-adjacent atoms, can combine to form a        bridging cycloalkyl or heterocycloalkyl;    -   R^(1′) and R^(2′) are independently, at each occurrence, —H,        —C₁-C₆ alkyl, —C₂-C₆ alkenyl, —C₃-C₈ cycloalkenyl, —C₂-C₆        alkynyl, —C₃-C₈ cycloalkyl, heterocyclyl, —OH, halogen, —NO₂,        —CN, —NHC₁-C₆ alkyl, —N(C₁-C₆ alkyl)₂, —S(O)₂N(C₁-C₆ alkyl)₂,        —N(C₁-C₆ alkyl)S(O)₂R⁵, —S(O)₂(C₁-C₆ alkyl), —(C₁-C₆        alkyl)S(O)₂R⁵, —C(O)C₁-C₆ alkyl, —CO₂C₁-C₆ alkyl, —N(C₁-C₆        alkyl)S(O)₂C₁-C₆ alkyl, or (CHR⁵)_(n)NR³R⁴, wherein each alkyl,        alkenyl, cycloalkenyl, alkynyl, cycloalkyl, or heterocyclyl is        optionally substituted with one or more substituents selected        from —OH, halogen, —NO₂, oxo, —CN, —R⁵, —OR³, —NR³, NR³R⁴,        —S(O)₂N(R³)₂—, —S(O)₂R⁵, —C(O)R⁵, —CO₂R⁵, —NR³S(O)₂R⁵, —S(O)R⁵,        —S(O)NR³R⁴, —NR³S(O)R⁵, heterocycle, aryl, or heteroaryl        containing 1-5 heteroatoms selected from the group consisting of        N, S, P, and O;    -   or R^(1′) and R^(2′) can combine with the carbon atom to which        they are both attached to form a spirocycle, spiroheterocycle,        or a spirocycloalkenyl;    -   or R^(1′) and R^(2′) can combine with R¹ or R² on adjacent atoms        to form a heterocycle, cycloalkyl, aryl, heteroaryl containing        1-5 heteroatoms selected from the group consisting of N, S, P,        and O, or cycloalkenyl;    -   or R^(1′) and R^(2′) can combine with R¹ or R² on non-adjacent        atoms, to form a bridging cycloalkyl or heterocycloalkyl;    -   R³ and R⁴ are independently, at each occurrence, —H, —C₁-C₆        alkyl, —C₂-C₆ alkenyl, —C₃-C₈ cycloalkenyl, —C₂-C₆ alkynyl,        —C₃-C₈ cycloalkyl, heterocyclyl, aryl, heteroaryl containing 1-5        heteroatoms selected from the group consisting of N, S, P, and        O, —S(O)₂N(C₁-C₆ alkyl)₂, —S(O)₂(C₁-C₆ alkyl), —(C₁-C₆        alkyl)S(O)₂R⁵, —C(O)C₁-C₆ alkyl, —CO₂C₁-C₆ alkyl, or        —(CHR⁵)_(n)N(C₁-C₆ alkyl)₂, wherein each alkyl, alkenyl,        cycloalkenyl, alkynyl, cycloalkyl, heterocyclyl, aryl, and        heteroaryl is optionally substituted with one or more        substituents selected from —OH, halogen, —NO₂, oxo, —CN, —R⁵,        —O(C₁-C₆ alkyl), —NH(C₁-C₆ alkyl), N(C₁-C₆ alkyl)₂,        —S(O)₂N(C₁-C₆ alkyl)₂, —S(O)₂NHC₁-C₆ alkyl, —C(O)C₁-C₆ alkyl,        —CO₂C₁-C₆ alkyl, —N(C₁-C₆ alkyl)S(O)₂C₁-C₆ alkyl, —S(O)R⁵,        —S(O)N(C₁-C₆ alkyl)₂, —N(C₁-C₆ alkyl)S(O)R⁵, heterocycle, aryl,        or heteroaryl containing 1-5 heteroatoms selected from the group        consisting of N, S, P, and O;    -   R⁵ is independently, at each occurrence, —H, —C₁-C₆ alkyl,        —C₂-C₆ alkenyl, —C₃-C₈ cycloalkenyl, —C₂-C₆ alkynyl, —C₃-C₈        cycloalkyl, heterocyclyl, aryl, heteroaryl containing 1-5        heteroatoms selected from the group consisting of N, S, P, and        O, —OH, halogen, —NO₂, —CN, —NH(C₁-C₆ alkyl), —N(C₁-C₆ alkyl)₂,        —S(O)₂NH(C₁-C₆ alkyl), —S(O)₂N(C₁-C₆ alkyl)₂, —S(O)₂C₁-C₆ alkyl,        —C(O)C₁-C₆ alkyl, —CO₂C₁-C₆ alkyl, —N(C₁-C₆ alkyl)SO₂C₁-C₆        alkyl, —S(O)(C₁-C₆ alkyl), —S(O)N(C₁-C₆ alkyl)₂, —N(C₁-C₆        alkyl)S(O)(C₁-C₆ alkyl) or —(CH₂)_(n)N(C₁-C₆ alkyl)₂;    -   each n is independently and at each occurrence an integer from 0        to 6; and    -   each m is independently and at each occurrence an integer from 1        to 6; and    -   provided that when X² and X⁴ are both C═O, X¹ is not NR³.

Another aspect of the disclosure relates to a method of treating adisease or disorder associated with HDAC, e.g., HDAC6 modulation in asubject in need thereof, comprising administering to the subject aneffective amount of a compound of Formula I.

Another aspect of the disclosure is directed to a method of inhibitingan HDAC, e.g., HDAC6. The method involves administering to a patient inneed thereof an effective amount of a compound of Formula I.

Another aspect of the disclosure relates to a compound of Formula I, ora pharmaceutically acceptable salt, prodrug, solvate, hydrate, tautomer,or isomer thereof, for use in treating or preventing a diseaseassociated with HDAC6 modulation.

Another aspect of the disclosure relates to the use of a compound ofFormula I, or a pharmaceutically acceptable salt, prodrug, solvate,hydrate, tautomer, or isomer thereof, in the manufacture of a medicamentfor treating or preventing a disease associated with HDAC6 modulation.

Another aspect of the disclosure is directed to pharmaceuticalcompositions comprising a compound of Formula I and a pharmaceuticallyacceptable carrier. The pharmaceutically acceptable carrier can furtherinclude an excipient, diluent, or surfactant. The pharmaceuticalcomposition can be effective for treating a disease or disorderassociated with HDAC, e.g., HDAC6 modulation in a subject in needthereof. The pharmaceutical compositions can comprise the compounds ofthe present disclosure for use in treating diseases described herein.The compositions can contain at least one compound of the disclosure anda pharmaceutically acceptable carrier. The disclosure also provides theuse of the compounds described herein in the manufacture of a medicamentfor the treatment of a disease associated with HDACs.

The present disclosure also provides methods for the treatment of humandiseases or disorders including, without limitation, oncological,neurological, inflammatory, autoimmune, infectious, metabolic,hematologic, or cardiovascular diseases or disorders.

The present disclosure also provides compounds that are useful ininhibiting of zinc-dependent HDAC enzymes, for instance HDAC6. Thesecompounds can also be useful in the treatment of diseases includingcancer.

The present disclosure further provides compounds that can inhibit anHDAC, e.g., HDAC6. In some embodiments, the efficacy-safety profile ofthe compounds of the current disclosure can be improved relative toother known HDAC (e.g. HDAC6) inhibitors. Additionally, the presenttechnology also has the advantage of being able to be used for a numberof different types of diseases, including cancer and non-cancerindications. Additional features and advantages of the presenttechnology will be apparent to one of skill in the art upon reading theDetailed Description of the Disclosure, below.

DETAILED DESCRIPTION OF THE DISCLOSURE

HDAC6 is a zinc-dependent histone deacetylase that has two catalyticdomains. HDAC6 can interact with and deacetylate non-histone proteins,including HSP90 and α-tubulin. Acetylation of HSP90 is associated withloss of function of HSP90. HDAC6 is also implicated in the degradationof misfolded proteins as part of the aggresome. Accordingly, inhibitionof HDAC6 can have downstream effects that can play a role in thedevelopment of certain diseases such as cancer. The present disclosureprovides inhibitors of an HDAC, e.g., HDAC6 and methods for using thesame to treat disease.

In a first aspect of the disclosure, compounds of the Formula I aredescribed:

and pharmaceutically acceptable salts, prodrugs, solvates, hydrates,tautomers, and isomers thereof, wherein R, L, X¹, X², X³, X⁴, Y¹, Y²,Y³, and Y⁴ are described as above.

The details of the disclosure are set forth in the accompanyingdescription below. Although methods and materials similar or equivalentto those described herein can be used in the practice or testing of thepresent disclosure, illustrative methods and materials are nowdescribed. Other features, objects, and advantages of the disclosurewill be apparent from the description and from the claims. In thespecification and the appended claims, the singular forms also includethe plural unless the context clearly dictates otherwise. Unless definedotherwise, all technical and scientific terms used herein have the samemeaning as commonly understood by one of ordinary skill in the art towhich this disclosure belongs. All patents and publications cited inthis specification are incorporated herein by reference in theirentireties.

Definitions

The articles “a” and “an” are used in this disclosure to refer to one ormore than one (e.g., to at least one) of the grammatical object of thearticle. By way of example, “an element” means one element or more thanone element.

The term “and/or” is used in this disclosure to mean either “and” or“or” unless indicated otherwise.

The term “optionally substituted” is understood to mean that a givenchemical moiety (e.g. an alkyl group) can (but is not required to) bebonded other substituents (e.g. heteroatoms). For instance, an alkylgroup that is optionally substituted can be a fully saturated alkylchain (e.g. a pure hydrocarbon). Alternatively, the same optionallysubstituted alkyl group can have substituents different from hydrogen.For instance, it can, at any point along the chain be bounded to ahalogen atom, a hydroxyl group, or any other substituent describedherein. Thus the term “optionally substituted” means that a givenchemical moiety has the potential to contain other functional groups,but does not necessarily have any further functional groups.

The term “aryl” refers to cyclic, aromatic hydrocarbon groups that have1 to 2 aromatic rings, including monocyclic or bicyclic groups such asphenyl, biphenyl or naphthyl. Where containing two aromatic rings(bicyclic, etc.), the aromatic rings of the aryl group may be joined ata single point (e.g., biphenyl), or fused (e.g., naphthyl). The arylgroup may be optionally substituted by one or more substituents, e.g., 1to 5 substituents, at any point of attachment. Exemplary substituentsinclude, but are not limited to, —H, -halogen, —O—C₁-C₆ alkyl, —C₁-C₆alkyl, —OC₂-C₆ alkenyl, —OC₂-C₆ alkynyl, —C₂-C₆ alkenyl, —C₂-C₆ alkynyl,—OH, —OP(O)(OH)₂, —OC(O)C₁-C₆ alkyl, —C(O)C₁-C₆ alkyl, —OC(O)OC₁-C₆alkyl, —NH₂, —NH(C₁-C₆ alkyl), —N(C₁-C₆ alkyl)₂, —S(O)₂—C₁-C₆ alkyl,—S(O)NHC₁-C₆ alkyl, and —S(O)N(C₁-C₆ alkyl)₂. The substituents canthemselves be optionally substituted. Furthermore when containing twofused rings the aryl groups herein defined may have an unsaturated orpartially saturated ring fused with a fully saturated ring. Exemplaryring systems of these aryl groups include indanyl, indenyl,tetrahydronaphthalenyl, and tetrahydrobenzoannulenyl.

Unless otherwise specifically defined, “heteroaryl” means a monovalentmonocyclic aromatic radical of 5 to 24 ring atoms or a polycyclicaromatic radical, containing one or more ring heteroatoms selected fromN, S, P, and O, the remaining ring atoms being C. Heteroaryl as hereindefined also means a bicyclic heteroaromatic group wherein theheteroatom is selected from N, S, P, and O. The aromatic radical isoptionally substituted independently with one or more substituentsdescribed herein. Examples include, but are not limited to, furyl,thienyl, pyrrolyl, pyridyl, pyrazolyl, pyrimidinyl, imidazolyl,isoxazolyl, oxazolyl, oxadiazolyl, pyrazinyl, indolyl, thiophen-2-yl,quinolyl, benzopyranyl, isothiazolyl, thiazolyl, thiadiazole, indazole,benzimidazolyl, thieno[3,2-b]thiophene, triazolyl, triazinyl,imidazo[1,2-b]pyrazolyl, furo[2,3-c]pyridinyl, imidazo[1,2-a]pyridinyl,indazolyl, pyrrolo[2,3-c]pyridinyl, pyrrolo[3,2-c]pyridinyl,pyrazolo[3,4-c]pyridinyl, thieno[3,2-c]pyridinyl,thieno[2,3-c]pyridinyl, thieno[2,3-b]pyridinyl, benzothiazolyl, indolyl,indolinyl, indolinonyl, dihydrobenzothiophenyl, dihydrobenzofuranyl,benzofuran, chromanyl, thiochromanyl, tetrahydroquinolinyl,dihydrobenzothiazine, dihydrobenzoxanyl, quinolinyl, isoquinolinyl,1,6-naphthyridinyl, benzo[de]isoquinolinyl,pyrido[4,3-b][1,6]naphthyridinyl, thieno[2,3-b]pyrazinyl, quinazolinyl,tetrazolo[1,5-a]pyridinyl, [1,2,4]triazolo[4,3-a]pyridinyl, isoindolyl,pyrrolo[2,3-b]pyridinyl, pyrrolo[3,4-b]pyridinyl,pyrrolo[3,2-b]pyridinyl, imidazo[5,4-b]pyridinyl,pyrrolo[1,2-a]pyrimidinyl, tetrahydro pyrrolo[1,2-a]pyrimidinyl,3,4-dihydro-2H-1λ²-pyrrolo[2,1-b]pyrimidine, dibenzo[b,d] thiophene,pyridin-2-one, furo[3,2-c]pyridinyl, furo[2,3-c]pyridinyl,1H-pyrido[3,4-b][1,4] thiazinyl, benzooxazolyl, benzoisoxazolyl,furo[2,3-b]pyridinyl, benzothiophenyl, 1,5-naphthyridinyl,furo[3,2-b]pyridine, [1,2,4]triazolo[1,5-a]pyridinyl, benzo[1,2,3]triazolyl, imidazo[1,2-a]pyrimidinyl,[1,2,4]triazolo[4,3-b]pyridazinyl, benzo[c][1,2,5]thiadiazolyl,benzo[c][1,2,5]oxadiazole, 1,3-dihydro-2H-benzo[d]imidazol-2-one,3,4-dihydro-2H-pyrazolo [1,5-b][1,2]oxazinyl,4,5,6,7-tetrahydropyrazolo[1,5-a]pyridinyl, thiazolo[5,4-d]thiazolyl,imidazo[2,1-b][1,3,4]thiadiazolyl, thieno[2,3-b]pyrrolyl, 3H-indolyl,and derivatives thereof. Furthermore when containing two fused rings theheteroaryl groups herein defined may have an unsaturated or partiallysaturated ring fused with a fully saturated ring. Exemplary ring systemsof these heteroaryl groups include indolinyl, indolinonyl,dihydrobenzothiophenyl, dihydrobenzofuran, chromanyl, thiochromanyl,tetrahydroquinolinyl, dihydrobenzothiazine,3,4-dihydro-1H-isoquinolinyl, 2,3-dihydrobenzofuran, indolinyl, indolyl,and dihydrobenzoxanyl.

“Alkyl” refers to a straight or branched chain saturated hydrocarbon.C₁-C₆ alkyl groups contain 1 to 6 carbon atoms. Examples of a C₁-C₆alkyl group include, but are not limited to, methyl, ethyl, propyl,butyl, pentyl, isopropyl, isobutyl, sec-butyl and tert-butyl, isopentyland neopentyl.

The term “alkenyl” means an aliphatic hydrocarbon group containing acarbon-carbon double bond and which may be straight or branched havingabout 2 to about 6 carbon atoms in the chain. Alkenyl groups can have 2to about 4 carbon atoms in the chain. Branched means that one or morelower alkyl groups such as methyl, ethyl, or propyl are attached to alinear alkenyl chain. Exemplary alkenyl groups include ethenyl,propenyl, n-butenyl, and i-butenyl. A C₂-C₆ alkenyl group is an alkenylgroup containing between 2 and 6 carbon atoms.

The term “alkynyl” means an aliphatic hydrocarbon group containing acarbon carbon triple bond and which may be straight or branched havingabout 2 to about 6 carbon atoms in the chain. Alkynyl groups can have 2to about 4 carbon atoms in the chain. Branched means that one or morelower alkyl groups such as methyl, ethyl, or propyl are attached to alinear alkynyl chain. Exemplary alkynyl groups include ethynyl,propynyl, n-butynyl, 2-butynyl, 3-methylbutynyl, and n-pentynyl. A C₂-C₆alkynyl group is an alkynyl group containing between 2 and 6 carbonatoms.

The term “cycloalkyl” means monocyclic or polycyclic saturated carbonrings containing 3-18 carbon atoms. Examples of cycloalkyl groupsinclude, without limitations, cyclopropyl, cyclobutyl, cyclopentyl,cyclohexyl, cycloheptanyl, cyclooctanyl, norboranyl, norborenyl,bicyclo[2.2.2]octanyl, or bicyclo[2.2.2]octenyl. A C₃-C₈ cycloalkyl is acycloalkyl group containing between 3 and 8 carbon atoms. A cycloalkylgroup can be fused (e.g., decalin) or bridged (e.g., norbornane).

The term “cycloalkenyl” means monocyclic, non-aromatic unsaturatedcarbon rings containing 3-18 carbon atoms. Examples of cycloalkenylgroups include, without limitation, cyclopentenyl, cyclohexenyl,cycloheptenyl, cyclooctenyl, and norborenyl. A C₃-C₈ cycloalkenyl is acycloalkenyl group containing between 3 and 8 carbon atoms.

The terms “heterocyclyl” or “heterocycloalkyl” or “heterocycle” refer tomonocyclic or polycyclic 3 to 24-membered rings containing carbon andheteroatoms taken from oxygen, nitrogen, or sulfur and wherein there isnot delocalized π electrons (aromaticity) shared among the ring carbonor heteroatoms. Heterocyclyl rings include, but are not limited to,oxetanyl, azetadinyl, tetrahydrofuranyl, pyrrolidinyl, oxazolinyl,oxazolidinyl, thiazolinyl, thiazolidinyl, pyranyl, thiopyranyl,tetrahydropyranyl, dioxalinyl, piperidinyl, morpholinyl,thiomorpholinyl, thiomorpholinyl S-oxide, thiomorpholinyl S-dioxide,piperazinyl, azepinyl, oxepinyl, diazepinyl, tropanyl, and homotropanyl.A heterocyclyl or heterocycloalkyl ring can also be fused or bridged,e.g., can be a bicyclic ring.

As used herein, the term “halo” or “halogen” means fluoro, chloro,bromo, or iodo.

The term “carbonyl” refers to a functional group composing a carbon atomdouble-bonded to an oxygen atom. It can be abbreviated herein as “oxo”,as C(O), or as C═O.

“Spirocycle” or “spirocyclic” means carbogenic bicyclic ring systemswith both rings connected through a single atom. The ring can bedifferent in size and nature, or identical in size and nature. Examplesinclude spiropentane, spriohexane, spiroheptane, spirooctane,spirononane, or spirodecane. One or both of the rings in a spirocyclecan be fused to another ring carbocyclic, heterocyclic, aromatic, orheteroaromatic ring. One or more of the carbon atoms in the spirocyclecan be substituted with a heteroatom (e.g., O, N, S, or P). A C₃-C₁₂spirocycle is a spirocycle containing between 3 and 12 carbon atoms. Oneor more of the carbon atoms can be substituted with a heteroatom.

The term “spirocyclic heterocycle” or “spiroheterocycle” is understoodto mean a spirocycle wherein at least one of the rings is a heterocycle(e.g., at least one of the rings is furanyl, morpholinyl, orpiperadinyl).

The disclosure also includes pharmaceutical compositions comprising aneffective amount of a disclosed compound and a pharmaceuticallyacceptable carrier. Representative “pharmaceutically acceptable salts”include, e.g., water-soluble and water-insoluble salts, such as theacetate, amsonate (4,4-diaminostilbene-2,2-disulfonate),benzenesulfonate, benzonate, bicarbonate, bisulfate, bitartrate, borate,bromide, butyrate, calcium, calcium edetate, camsylate, carbonate,chloride, citrate, clavulariate, dihydrochloride, edetate, edisylate,estolate, esylate, fumarate, gluceptate, gluconate, glutamate,glycollylarsanilate, hexafluorophosphate, hexylresorcinate, hydrabamine,hydrobromide, hydrochloride, hydroxynaphthoate, iodide, sethionate,lactate, lactobionate, laurate, magnesium, malate, maleate, mandelate,mesylate, methylbromide, methylnitrate, methylsulfate, mucate,napsylate, nitrate, N-methylglucamine ammonium salt,3-hydroxy-2-naphthoate, oleate, oxalate, palmitate, pamoate(1,1-methene-bis-2-hydroxy-3-naphthoate, einbonate), pantothenate,phosphate/diphosphate, picrate, polygalacturonate, propionate,p-toluenesulfonate, salicylate, stearate, subacetate, succinate,sulfate, sulfosalicylate, suramate, tannate, tartrate, teoclate,tosylate, triethiodide, and valerate salts.

The term “stereoisomers” refers to the set of compounds which have thesame number and type of atoms and share the same bond connectivitybetween those atoms, but differ in three dimensional structure. The term“stereoisomer” refers to any member of this set of compounds.

The term “diastereomers” refers to the set of stereoisomers which cannotbe made superimposable by rotation around single bonds. For example,cis- and trans-double bonds, endo- and exo-substitution on bicyclic ringsystems, and compounds containing multiple stereogenic centers withdifferent relative configurations are considered to be diastereomers.The term “diastereomer” refers to any member of this set of compounds.In some examples presented, the synthetic route may produce a singlediastereomer or a mixture of diastereomers. In some cases thesediastereomers were separated and in other cases a wavy bond is used toindicate the structural element where configuration is variable.

The term “enantiomers” refers to a pair of stereoisomers which arenon-superimposable mirror images of one another. The term “enantiomer”refers to a single member of this pair of stereoisomers. The term“racemic” refers to a 1:1 mixture of a pair of enantiomers.

The term “tautomers” refers to a set of compounds that have the samenumber and type of atoms, but differ in bond connectivity and are inequilibrium with one another. A “tautomer” is a single member of thisset of compounds. Typically a single tautomer is drawn but it isunderstood that this single structure is meant to represent all possibletautomers that might exist. Examples include enol-ketone tautomerism.When a ketone is drawn it is understood that both the enol and ketoneforms are part of the disclosure.

An “effective amount” when used in connection with a compound is anamount effective for treating or preventing a disease in a subject asdescribed herein.

The term “carrier”, as used in this disclosure, encompasses carriers,excipients, and diluents and means a material, composition or vehicle,such as a liquid or solid filler, diluent, excipient, solvent orencapsulating material, involved in carrying or transporting apharmaceutical agent from one organ, or portion of the body, to anotherorgan, or portion of the body of a subject.

The term “treating” with regard to a subject, refers to improving atleast one symptom of the subject's disorder. Treating includes curing,improving, or at least partially ameliorating the disorder.

The term “disorder” is used in this disclosure to mean, and is usedinterchangeably with, the terms disease, condition, or illness, unlessotherwise indicated.

The term “administer”, “administering”, or “administration” as used inthis disclosure refers to either directly administering a disclosedcompound or pharmaceutically acceptable salt of the disclosed compoundor a composition to a subject, or administering a prodrug derivative oranalog of the compound or pharmaceutically acceptable salt of thecompound or composition to the subject, which can form an equivalentamount of active compound within the subject's body.

The term “prodrug,” as used in this disclosure, means a compound whichis convertible in vivo by metabolic means (e.g., by hydrolysis) to adisclosed compound. Furthermore, as used herein a prodrug is a drugwhich is inactive in the body, but is transformed in the body typicallyeither during absorption or after absorption from the gastrointestinaltract into the active compound. The conversion of the prodrug into theactive compound in the body may be done chemically or biologically(e.g., using an enzyme).

The term “solvate” refers to a complex of variable stoichiometry formedby a solute and solvent. Such solvents for the purpose of the disclosuremay not interfere with the biological activity of the solute. Examplesof suitable solvents include, but are not limited to, water, MeOH, EtOH,and AcOH. Solvates wherein water is the solvent molecule are typicallyreferred to as hydrates. Hydrates include compositions containingstoichiometric amounts of water, as well as compositions containingvariable amounts of water.

The term “isomer” refers to compounds that have the same composition andmolecular weight but differ in physical and/or chemical properties. Thestructural difference may be in constitution (geometric isomers) or inthe ability to rotate the plane of polarized light (stereoisomers). Withregard to stereoisomers, the compounds of Formula I may have one or moreasymmetric carbon atom and may occur as racemates, racemic mixtures andas individual enantiomers or diastereomers.

A “patient” or “subject” is a mammal, e.g., a human, mouse, rat, guineapig, dog, cat, horse, cow, pig, or non-human primate, such as a monkey,chimpanzee, baboon or rhesus.

In another embodiment of the disclosure are described compounds of theFormula IA:

and pharmaceutically acceptable salts, prodrugs, solvates, hydrates,tautomers or isomer thereof; where R, L, X¹, X², X³, X⁴, Y¹, Y³, and Y⁴are defined as above in Formula I.

In one embodiment of the compounds of Formula IA, X⁴ is CR¹R².

In another embodiment of the compounds of Formula IA, X¹ is NR³, O, orC═O.

In another embodiment of the compounds of Formula IA, X¹ is O.

In another embodiment of the compounds of Formula IA, X¹ is O and X⁴ isCR¹R².

In some embodiments of the disclosure, the compounds of Formula IA maybe of the Formula IA-1:

For instance, in some embodiments of Formula IA-1, the compounds can beof the Formula IA-1a, Formula IA-1b, Formula IA-1c, Formula IA-1d,Formula IA-1e, or Formula IA-1f:

In other embodiments of the compounds of Formula IA, the compound is ofthe Formula IA-2:

In yet other another embodiments of the compounds of Formula IA, thecompound is of the Formula IA-3:

In yet other embodiments of the compounds of Formula IA, the compound isof the Formula IA-4:

In yet other another embodiments of the compounds of Formula IA, thecompound is of the Formula IA-5:

In yet other another embodiments of the compounds of Formula IA, thecompound is of the Formula IA-6:

In yet other another embodiments of the compounds of Formula IA, thecompound is of the Formula IA-7:

In other embodiments of the compounds of Formula IA, the compound is ofthe Formula IA-8:

In a further embodiment of the compounds of Formula IA, the compound isalso of the Formula IA-9:

In another embodiment of the compounds of Formula IA, the compound is ofthe Formula IA-10:

In another embodiment of the compounds of Formula IA, the compound is ofthe Formula IA-11:

In one embodiment of the disclosure are also disclosed compounds of theFormula IB:

and pharmaceutically acceptable salts, prodrugs, solvates, hydrates,enantiomers and isomers thereof where R, L, X¹, X², X³, X⁴, Y¹, Y², andY⁴ are defined as above in Formula I.

In one embodiment of the compounds of Formula IB, X⁴ is CR¹R².

In another embodiment of the compounds of Formula IB, X¹ is NR³, O, orC═O.

In another embodiment of the compounds of Formula IB, X¹ is O.

In another embodiment of the compounds of Formula IB, X¹ is O and X⁴ isCR¹R².

In another embodiment of the compounds of Formula IB, X¹ is N, X² isC═O, and X⁴ is CR¹R².

In some embodiments of the disclosure, the compounds of Formula IB, maybe of the Formula IB-1:

In yet other embodiments of the compounds of Formula IB, the compound isof the Formula (IB-2):

For instance, in some embodiments, the compounds of the disclosure canbe of the Formula IB-2a:

In other embodiments of the compounds of Formula IB, the compound mayalso be of the Formula IB-3:

In other embodiments of the compounds of Formula IB, the compound is ofthe Formula (IB-4):

In a further embodiment of the compounds of Formula IB, the compound isalso of the Formula IB-5.

In some embodiments of Formula (I), X¹ is O. In another embodiment, X¹is O and X² is CR¹R². In yet another embodiment, X¹ is O, X² is CR¹R²,and X³ is CR^(1′)R^(2′). In another embodiment, X¹ is O, X² is CR¹R², X³is CR^(1′)R^(2′), and X⁴ is CR¹R². In yet another embodiment, X¹ is O,X² is CR¹R², X³ is CR^(1′)R^(2′), X⁴ is CR¹R², and Y¹ is CR¹. In anotherembodiment, X¹ is O, X² is CR¹R², X³ is CR^(1′)R^(2′), X⁴ is CR¹R², Y¹is CR¹, and Y³ is CR¹. In yet another embodiment, X¹ is O, X² is CR¹R²,X³ is CR^(1′)R^(2′), X⁴ is CR¹R², Y¹ is CR¹, Y³ is CR¹, and Y⁴ is CR¹.In another embodiment, X¹ is O, X² is CR¹R², X³ is CR^(1′)R^(2′), X⁴ isCR¹R², Y¹ is CR¹, Y³ is CR¹, Y⁴ is CR¹, and Y² is C. In yet anotherembodiment, X¹ is O, X² is CR¹R², X³ is CR^(1′)R^(2′), X⁴ is CR¹R², Y¹is CR¹, Y³ is CR¹, Y⁴ is CR¹, Y² is C, and L is —C(O)—. In anotherembodiment, X¹ is O, X² is CR¹R², X³ is CR^(1′)R^(2′), X⁴ is CR¹R², Y¹is CR¹, Y³ is CR¹, Y⁴ is CR¹, Y² is C, L is —C(O)—, and R¹ is H or—C₁-C₆ alkyl. In another embodiment, X¹ is O, X² is CR¹R², X³ is CR¹R²,X⁴ is CR¹R², Y¹ is CR¹, Y³ is CR¹, Y⁴ is CR¹, Y² is C, L is —C(O)—, andR¹ and R², when on non-adjacent atoms, combine to form a bridgingcycloalkyl or heterocycloalkyl.

In another embodiment, X¹ is O, X² is CR¹R², X³ is CR^(1′)R^(2′), X⁴ isCR¹R², Y¹ is CR¹, Y³ is CR¹, Y⁴ is CR¹, Y² is C, and L is—C(O)(CR¹R²)_(m)—. In yet another embodiment, X¹ is O, X² is CR¹R², X³is CR^(1′)R^(2′), X⁴ is CR¹R², Y¹ is CR¹, Y³ is CR¹, Y⁴ is CR¹, Y² is C,L is —C(O)(CR¹R²)_(m)—, and R¹ is H or —C₁-C₆ alkyl. In anotherembodiment, X¹ is O, X² is CR¹R², X³ is CR^(1′)R^(2′), X⁴ is CR¹R², Y¹is CR¹, Y³ is CR¹, Y⁴ is CR¹, Y² is C, L is —C(O)(CR¹R²)_(m)—, and R¹and R², when on non-adjacent atoms, combine to form a bridgingcycloalkyl or heterocycloalkyl.

In another embodiment, X¹ is O, X² is CR¹R², X³ is CR^(1′)R^(2′), X⁴ isCR¹R², Y¹ is CR¹, Y³ is CR¹, Y⁴ is CR¹, Y² is C, and L is—C(O)(CR¹R²)_(m)O—. In yet another embodiment, X¹ is O, X² is CR¹R², X³is CR^(1′)R^(2′), X⁴ is CR¹R², Y¹ is CR¹, Y³ is CR¹, Y⁴ is CR¹, Y² is C,L is —C(O)(CR¹R²)_(m)O—, and R¹ is H or —C₁-C₆ alkyl. In anotherembodiment, X¹ is O, X² is CR¹R², X³ is CR^(1′)R^(2′), X⁴ is CR¹R², Y¹is CR¹, Y³ is CR¹, Y⁴ is CR¹, Y² is C, L is —C(O)(CR¹R²)_(m)O—, and R¹and R², when on non-adjacent atoms, combine to form a bridgingcycloalkyl or heterocycloalkyl.

In another embodiment, X¹ is O, X² is CR¹R², X³ is CR^(1′)R^(2′), X⁴ isCR¹R², Y¹ is CR¹, and Y³ is C. In yet another embodiment, X¹ is O, X² isCR¹R², X³ is CR^(1′)R^(2′), X⁴ is CR¹R², Y¹ is CR¹, Y³ is C, and Y⁴ isCR¹. In another embodiment, X¹ is O, X² is CR¹R², X³ is CR^(1′)R^(2′),X⁴ is CR¹R², Y¹ is CR¹, Y³ is C, Y⁴ is CR¹, and Y² is CR¹. In yetanother embodiment, X¹ is O, X² is CR¹R², X³ is CR^(1′)R^(2′), X⁴ isCR¹R², Y¹ is CR¹, Y³ is C, Y⁴ is CR¹, Y² is CR¹, and L is —C(O)—. Inanother embodiment, X¹ is O, X² is CR¹R², X³ is CR^(1′)R^(2′), X⁴ isCR¹R², Y¹ is CR¹, Y³ is C, Y⁴ is CR¹, Y² is CR¹, L is —C(O)—, and R¹ isH or —C₁-C₆ alkyl. In another embodiment, X¹ is O, X² is CR¹R², X³ isCR^(1′)R^(2′), X⁴ is CR¹R², Y¹ is CR¹, Y³ is CR¹, Y⁴ is CR¹, Y² is C, Lis —C(O)—, and R¹ and R², when on non-adjacent atoms, combine to form abridging cycloalkyl or heterocycloalkyl.

In yet another embodiment, X¹ is O, X² is CR¹R², X³ is CR^(1′)R^(2′), X⁴is CR¹R², Y¹ is CR¹, Y³ is C, Y⁴ is CR¹, Y² is CR¹, and L is—C(O)(CR¹R²)_(m)—. In another embodiment, X¹ is O, X² is CR¹R², X³ isCR^(1′)R^(2′), X⁴ is CR¹R², Y¹ is CR¹, Y³ is C, Y⁴ is CR¹, Y² is CR¹, Lis —C(O)(CR¹R²)_(m)—, and R¹ is H or —C₁-C₆ alkyl. In anotherembodiment, X¹ is O, X² is CR¹R², X³ is CR^(1′)R^(2′), X⁴ is CR¹R², Y¹is CR¹, Y³ is C, Y⁴ is CR¹, Y² is CR¹, L is —C(O)(CR¹R²)_(m)—, and R¹and R², when on non-adjacent atoms, combine to form a bridgingcycloalkyl or heterocycloalkyl.

In yet another embodiment, X¹ is O, X² is CR¹R², X³ is CR^(1′)R^(2′), X⁴is CR¹R², Y¹ is CR¹, Y³ is C, Y⁴ is CR¹, Y² is CR¹, and L is—C(O)(CR¹R²)_(m)O—. In another embodiment, X¹ is O, X² is CR¹R², X³ isCR^(1′)R^(2′), X⁴ is CR¹R², Y¹ is CR¹, Y³ is C, Y⁴ is CR¹, Y² is CR¹, Lis —C(O)(CR¹R²)_(m)O—, and R¹ is H or —C₁-C₆ alkyl. In anotherembodiment, X¹ is O, X² is CR¹R², X³ is CR^(1′)R^(2′), X⁴ is CR¹R², Y¹is CR¹, Y³ is C, Y⁴ is CR¹, Y² is CR¹, L is —C(O)(CR¹R²)_(m)O—, and R¹and R², when on non-adjacent atoms, combine to form a bridgingcycloalkyl or heterocycloalkyl.

In some embodiments of Formula (I), X¹ is NR³. In another embodiment, X¹is NR³ and X² is C═O. In yet another embodiment, X¹ is NR³, X² is C═O,and X³ is CR^(1′)R^(2′). In another embodiment, X¹ is NR³, X² is C═O, X³is CR^(1′)R^(2′), and X⁴ is CR¹R². In yet another embodiment, X¹ is NR³,X² is C═O, X³ is CR^(1′)R^(2′), X⁴ is CR¹R², and Y¹ is CR¹. In anotherembodiment, X¹ is NR³, X² is C═O, X³ is CR^(1′)R^(2′), X⁴ is CR¹R², Y isCR¹, and Y³ is CR¹. In yet another embodiment, X¹ is NR³, X² is C═O, X³is CR^(1′)R^(2′), X⁴ is CR¹R², Y¹ is CR¹, Y³ is CR¹, and Y⁴ is CR¹. Inanother embodiment, X¹ is NR³, X² is C═O, X³ is CR^(1′)R^(2′), X⁴ isCR¹R², Y is CR¹, Y³ is CR¹, Y⁴ is CR¹, and Y² is C. In yet anotherembodiment, X¹ is NR³, X² is C═O, X³ is CR^(1′)R^(2′), X⁴ is CR¹R², Y¹is CR¹, Y³ is CR¹, Y⁴ is CR¹, Y² is C, and L is —C(O)—. In anotherembodiment, X¹ is NR³, X² is C═O, X³ is CR^(1′)R^(2′), X⁴ is CR¹R², Y¹is CR¹, Y³ is CR¹, Y⁴ is CR¹, Y² is C, L is —C(O)—, and R¹ is H or—C₁-C₆ alkyl. In another embodiment, X¹ is NR³, X² is C═O, X³ isCR^(1′)R^(2′), X⁴ is CR¹R², Y¹ is CR¹, Y³ is CR¹, Y⁴ is CR¹, Y² is C, Lis —C(O)—, and R¹ and R², when on non-adjacent atoms, combine to form abridging cycloalkyl or heterocycloalkyl.

In another embodiment, X¹ is NR³, X² is C═O, X³ is CR^(1′)R^(2′), X⁴ isCR¹R², Y¹ is CR¹, Y³ is CR¹, Y⁴ is CR¹, Y² is C, and L is—C(O)(CR¹R²)_(m)—. In another embodiment, X¹ is NR³, X² is C═O, X³ isCR^(1′)R^(2′), X⁴ is CR¹R², Y is CR¹, Y³ is CR¹, Y⁴ is CR¹, Y² is C, Lis —C(O)(CR¹R²)_(m)—, and R¹ is H or —C₁-C₆ alkyl. In anotherembodiment, X¹ is NR³, X² is C═O, X³ is CR^(1′)R^(2′), X⁴ is CR¹R², Y¹is CR¹, Y³ is CR¹, Y⁴ is CR¹, Y² is C, L is —C(O)(CR¹R²)_(m)—, and R¹and R², when on non-adjacent atoms, combine to form a bridgingcycloalkyl or heterocycloalkyl.

In yet another embodiment, X¹ is NR³, X² is C═O, X³ is CR^(1′)R^(2′), X⁴is CR¹R², Y¹ is CR¹, Y³ is CR¹, Y⁴ is CR¹, Y² is C, and L is—C(O)(CR¹R²)_(m)O—. In another embodiment, X¹ is NR³, X² is C═O, X³ isCR^(1′)R^(2′), X⁴ is CR¹R², Y¹ is CR¹, Y³ is CR¹, Y⁴ is CR¹, Y² is C, Lis —C(O)(CR¹R²)_(m)O—, and R¹ is H or —C₁-C₆ alkyl. In anotherembodiment, X¹ is NR, X² is C═O, X³ is CR^(1′)R^(2′), X⁴ is CR¹R², Y¹ isCR¹, Y³ is CR¹, Y⁴ is CR¹, Y² is C, L is —C(O)(CR¹R²)_(m)O—, and R¹ andR², when on non-adjacent atoms, combine to form a bridging cycloalkyl orheterocycloalkyl.

In another embodiment, X¹ is NR³, X² is C═O, X³ is CR^(1′)R^(2′), X⁴ isCR¹R², Y¹ is CR¹, and Y³ is C. In yet another embodiment, X¹ is NR³, X²is C═O, X³ is CR^(1′)R^(2′), X⁴ is CR¹R², Y¹ is CR¹, Y³ is C, and Y⁴ isCR¹. In another embodiment, X¹ is NR, X² is C═O, X³ is CR^(1′)R^(2′), X⁴is CR¹R², Y¹ is CR¹, Y³ is C, Y⁴ is CR¹, and Y² is CR¹. In yet anotherembodiment, X¹ is NR, X² is C═O, X³ is CR^(1′)R^(2′), X⁴ is CR¹R², Y¹ isCR¹, Y³ is C, Y⁴ is CR¹, Y² is CR¹, and L is —C(O)—. In anotherembodiment, X¹ is NR³, X² is C═O, X³ is CR^(1′)R^(2′), X⁴ is CR¹R², Y¹is CR¹, Y³ is C, Y⁴ is CR¹, Y² is CR¹, L is —C(O)—, and R¹ is H or—C₁-C₆ alkyl. In another embodiment, X¹ is NR, X² is C═O, X³ isCR^(1′)R^(2′), X⁴ is CR¹R², Y¹ is CR¹, Y³ is C, Y⁴ is CR¹, Y² is CR¹, Lis —C(O)—, and R¹ and R², when on non-adjacent atoms, combine to form abridging cycloalkyl or heterocycloalkyl.

In another embodiment, X¹ is NR³, X² is C═O, X³ is CR^(1′)R^(2′), X⁴ isCR¹R², Y¹ is CR¹, Y³ is C, Y⁴ is CR¹, Y² is CR¹, and L is—C(O)(CR¹R²)_(m)—. In another embodiment, X¹ is NR³, X² is C═O, X³ isCR^(1′)R^(2′), X⁴ is CR¹R², Y¹ is CR¹, Y³ is C, Y⁴ is CR¹, Y² is CR¹, Lis —C(O)(CR¹R²)_(m)—, and R¹ is H or —C₁-C₆ alkyl. In anotherembodiment, X¹ is NR, X² is C═O, X³ is CR^(1′)R^(2′), X⁴ is CR¹R², Y¹ isCR¹, Y³ is C, Y⁴ is CR¹, Y² is CR¹, L is —C(O)(CR¹R²)_(m)—, and R¹ andR², when on non-adjacent atoms, combine to form a bridging cycloalkyl orheterocycloalkyl.

In yet another embodiment, X¹ is NR³, X² is C═O, X³ is CR^(1′)R^(2′), X⁴is CR¹R², Y¹ is CR¹, Y³ is C, Y⁴ is CR¹, Y² is CR¹, and L is—C(O)(CR¹R²)_(m)O—. In another embodiment, X¹ is NR³, X² is C═O, X³ isCR^(1′)R^(2′), X⁴ is CR¹R², Y¹ is CR¹, Y³ is C, Y⁴ is CR¹, Y² is CR¹, Lis —C(O)(CR¹R²)_(m)O—, and R¹ is H or —C₁-C₆ alkyl. In anotherembodiment, X¹ is NR, X² is C═O, X³ is CR^(1′)R^(2′), X⁴ is CR¹R², Y¹ isCR¹, Y³ is C, Y⁴ is CR¹, Y² is CR¹, L is —C(O)(CR¹R²)_(m)O—, and R¹ andR², when on non-adjacent atoms, combine to form a bridging cycloalkyl orheterocycloalkyl.

In yet another embodiment, X¹ is O, X² is CR¹R², X³ is CR^(1′)R^(2′), X⁴is CR¹R², and Y¹ is N. In another embodiment, X¹ is O, X² is CR¹R², X³is CR^(1′)R^(2′), X⁴ is CR¹R², Y¹ is N, and Y³ is CR¹. In yet anotherembodiment, X¹ is O, X² is CR¹R², X³ is CR^(1′)R^(2′), X⁴ is CR¹R², Y¹is N, Y³ is CR¹, and Y⁴ is CR¹. In another embodiment, X is O, X² isCR¹R², X³ is CR^(1′)R^(2′), X⁴ is CR¹R², Y¹ is N, Y³ is CR¹, Y⁴ is CR¹,and Y² is C. In yet another embodiment, X¹ is O, X² is CR¹R², X³ isCR^(1′)R^(2′), X⁴ is CR¹R², Y¹ is N, Y³ is CR¹, Y⁴ is CR¹, Y² is C, andL is —C(O)—. In another embodiment, X¹ is O, X² is CR¹R², X³ isCR^(1′)R^(2′), X⁴ is CR¹R², Y¹ is N, Y³ is CR¹, Y⁴ is CR¹, Y² is C, L is—C(O)—, and R¹ is H or —C₁-C₆ alkyl. In another embodiment, X¹ is O, X²is CR¹R², X³ is CR^(1′)R^(2′), X⁴ is CR¹R², Y¹ is N, Y³ is CR, Y⁴ is CR,Y² is C, L is —C(O)—, and R¹ and R², when on non-adjacent atoms, combineto form a bridging cycloalkyl or heterocycloalkyl.

In another embodiment, X¹ is O, X² is CR¹R², X³ is CR^(1′)R^(2′), X⁴ isCR¹R², Y¹ is N, Y³ is CR¹, Y⁴ is CR¹, Y² is C, and L is—C(O)(CR¹R²)_(m)—. In another embodiment, X¹ is O, X² is CR¹R², X³ isCR^(1′)R^(2′), X⁴ is CR¹R², Y¹ is N, Y³ is CR¹, Y⁴ is CR¹, Y² is C, L is—C(O)(CR¹R²)_(m)—, and R¹ is H or —C₁-C₆ alkyl. In another embodiment,X¹ is O, X² is CR¹R², X³ is CR^(1′)R^(2′), X⁴ is CR¹R², Y¹ is N¹, Y³ isCR¹, Y⁴ is CR¹, Y² is C, L is —C(O)(CR¹R²)_(m)—, and R¹ and R², when onnon-adjacent atoms, combine to form a bridging cycloalkyl orheterocycloalkyl.

In yet another embodiment, X¹ is O, X² is CR¹R², X³ is CR^(1′)R^(2′), X⁴is CR¹R², Y¹ is N, Y³ is CR¹, Y⁴ is CR¹, Y² is C, and L is—C(O)(CR¹R²)_(m)O—. In another embodiment, X¹ is O, X² is CR¹R², X³ isCR^(1′)R^(2′), X⁴ is CR¹R², Y¹ is N, Y³ is CR¹, Y⁴ is CR¹, Y² is C, L is—C(O)(CR¹R²)_(m)O—, and R¹ is H or —C₁-C₆ alkyl. In another embodiment,X¹ is O, X² is CR¹R², X³ is CR^(1′)R^(2′), X⁴ is CR¹R², Y¹ is N, Y³ isCR¹, Y⁴ is CR¹, Y² is C, L is —C(O)(CR¹R²)_(m)O—, and R¹ and R², when onnon-adjacent atoms, combine to form a bridging cycloalkyl orheterocycloalkyl.

In another embodiment, X¹ is O, X² is CR¹R², X³ is CR^(1′)R^(2′), X⁴ isCR¹R², Y¹ is N, and Y³ is C. In yet another embodiment, X¹ is O, X² isCR¹R², X³ is CR^(1′)R^(2′), X⁴ is CR¹R², Y¹ is N, Y³ is C, and Y⁴ isCR¹. In another embodiment, X¹ is O, X² is CR¹R², X³ is CR^(1′)R^(2′),X⁴ is CR¹R², Y¹ is N, Y³ is C, Y⁴ is CR¹, and Y² is CR¹. In yet anotherembodiment, X¹ is O, X² is CR¹R², X³ is CR^(1′)R^(2′), X⁴ is CR¹R², Y¹is N, Y³ is C, Y⁴ is CR¹, Y² is CR¹, and L is —C(O)—. In anotherembodiment, X¹ is O, X² is CR¹R², X³ is CR^(1′)R^(2′), X⁴ is CR¹R², Y¹is N, Y³ is C, Y⁴ is CR¹, Y² is CR¹, L is —C(O)—, and R¹ is H or —C₁-C₆alkyl. In another embodiment, X¹ is O, X² is CR¹R², X³ is CR^(1′)R^(2′),X⁴ is CR¹R², Y¹ is N, Y³ is C, Y⁴ is CR¹, Y² is CR¹, L is —C(O)—, and R¹and R², when on non-adjacent atoms, combine to form a bridgingcycloalkyl or heterocycloalkyl.

In another embodiment, X¹ is O, X² is CR¹R², X³ is CR^(1′)R^(2′), X⁴ isCR¹R², Y¹ is N, Y³ is C, Y⁴ is CR¹, Y² is CR¹, and L is—C(O)(CR¹R²)_(m)—. In another embodiment, X¹ is O, X² is CR¹R², X³ isCR^(1′)R^(2′), X⁴ is CR¹R², Y¹ is N, Y³ is C, Y⁴ is CR¹, Y² is CR¹, L is—C(O)(CR¹R²)_(m)—, and R¹ is H or —C₁-C₆ alkyl. In another embodiment,X¹ is O, X² is CR¹R², X³ is CR^(1′)R^(2′), X⁴ is CR¹R², Y¹ is N¹, Y³ isC, Y⁴ is CR¹, Y² is CR¹, L is —C(O)(CR¹R²)_(m)—, and R¹ and R², when onnon-adjacent atoms, combine to form a bridging cycloalkyl orheterocycloalkyl.

In yet another embodiment, X¹ is O, X² is CR¹R², X³ is CR^(1′)R^(2′), X⁴is CR¹R², Y¹ is N, Y³ is C, Y⁴ is CR¹, Y² is CR¹, and L is—C(O)(CR¹R²)_(m)O—. In another embodiment, X¹ is O, X² is CR¹R², X³ isCR^(1′)R^(2′), X⁴ is CR¹R², Y¹ is N, Y³ is C, Y⁴ is CR¹, Y² is CR¹, L is—C(O)(CR¹R²)_(m)O—, and R¹ is H or —C₁-C₆ alkyl. In another embodiment,X¹ is O, X² is CR¹R², X³ is CR¹R², X⁴ is CR¹R², Y¹ is N, Y³ is C, Y⁴ isCR¹, Y² is CR¹, L is —C(O)(CR¹R²)_(m)O—, and R¹ and R², when onnon-adjacent atoms, combine to form a bridging cycloalkyl orheterocycloalkyl.

In another embodiment, X¹ is NR³, X² is C═O, X³ is CR^(1′)R^(2′), X⁴ isCR¹R², and Y¹ is N. In another embodiment, X¹ is NR³, X² is C═O, X³ isCR^(1′)R^(2′), X⁴ is CR¹R², Y¹ is N, and Y³ is CR¹. In yet anotherembodiment, X¹ is NR³, X² is C═O, X³ is CR^(1′)R^(2′), X⁴ is CR¹R², Y¹is N, Y³ is CR¹, and Y⁴ is CR¹. In another embodiment, X¹ is NR, X² isC═O, X³ is CR^(1′)R^(2′), X⁴ is CR¹R², Y¹ is N, Y³ is CR¹, Y⁴ is CR¹,and Y² is C. In yet another embodiment, X¹ is NR³, X² is C═O, X³ isCR^(1′)R^(2′), X⁴ is CR¹R², Y¹ is N, Y³ is CR¹, Y⁴ is CR¹, Y² is C, andL is —C(O)—. In another embodiment, X¹ is NR³, X² is C═O, X³ isCR^(1′)R^(2′), X⁴ is CR¹R², Y¹ is N, Y³ is CR¹, Y⁴ is CR¹, Y² is C, L is—C(O)—, and R¹ is H or —C₁-C₆ alkyl. In another embodiment, X¹ is NR, X²is C═O, X³ is CR^(1′)R^(2′), X⁴ is CR¹R², Y¹ is N, Y³ is CR¹, Y⁴ is CR¹,Y² is C, L is —C(O)—, and R¹ and R², when on non-adjacent atoms, combineto form a bridging cycloalkyl or heterocycloalkyl.

In another embodiment, X¹ is NR³, X² is C═O, X³ is CR^(1′)R^(2′), X⁴ isCR¹R², Y¹ is N, Y³ is CR¹, Y⁴ is CR¹, Y² is C, and L is—C(O)(CR¹R²)_(m)—. In yet another embodiment, X¹ is NR³, X² is C═O, X³is CR^(1′)R^(2′), X⁴ is CR¹R², Y¹ is N, Y³ is CR¹, Y⁴ is CR¹, Y² is C, Lis —C(O)(CR¹R²)_(m)—, and R¹ is H or —C₁-C₆ alkyl. In anotherembodiment, X¹ is NR³, X² is C═O, X³ is CR¹R², X⁴ is CR¹R², Y¹ is N, Y³is CR¹, Y⁴ is CR¹, Y² is C, L is —C(O)(CR¹R²)_(m)—, and R¹ and R², whenon non-adjacent atoms, combine to form a bridging cycloalkyl orheterocycloalkyl.

In another embodiment, X¹ is NR³, X² is C═O, X³ is CR^(1′)R^(2′), X⁴ isCR¹R², Y¹ is N, Y³ is CR¹, Y⁴ is CR¹, Y² is C, and L is—C(O)(CR¹R²)_(m)O—. In yet another embodiment, X¹ is NR³, X² is C═O, X³is CR^(1′)R^(2′), X⁴ is CR¹R², Y¹ is N, Y³ is CR¹, Y⁴ is CR¹, Y² is C, Lis —C(O)(CR¹R²)_(m)O—, and R¹ is H or —C₁-C₆ alkyl. In anotherembodiment, X¹ is NR³, X² is C═O, X³ is CR^(1′)R^(2′), X⁴ is CR¹R², Y¹is N, Y³ is CR¹, Y⁴ is CR¹, Y² is C, L is —C(O)(CR¹R²)_(m)O—, and R¹ andR², when on non-adjacent atoms, combine to form a bridging cycloalkyl orheterocycloalkyl.

In another embodiment, X¹ is NR³, X² is C═O, X³ is CR^(1′)R^(2′), X⁴ isCR¹R², Y¹ is N, and Y³ is C. In yet another embodiment, X¹ is NR³, X² isC═O, X³ is CR^(1′)R^(2′), X⁴ is CR¹R², Y¹ is N, Y³ is C, and Y⁴ is CR¹.In another embodiment, X¹ is NR³, X² is C═O, X³ is CR^(1′)R^(2′), X⁴ isCR¹R², Y¹ is N, Y³ is C, Y⁴ is CR¹, and Y² is CR¹. In yet anotherembodiment, X¹ is NR³, X² is C═O, X³ is CR^(1′)R^(2′), X⁴ is CR¹R², Y¹is N, Y³ is C, Y⁴ is CR¹, Y² is CR¹, and L is —C(O)—. In anotherembodiment, X¹ is NR³, X² is C═O, X³ is CR^(1′)R^(2′), X⁴ is CR¹R², Y¹is N, Y³ is C, Y⁴ is CR¹, Y² is CR¹, L is —C(O)—, and R¹ is H or —C₁-C₆alkyl. In another embodiment, X¹ is NR³, X² is C═O, X³ is CR^(1′)R^(2′),X⁴ is CR¹R², Y¹ is N, Y³ is C, Y⁴ is CR¹, Y² is CR¹, L is —C(O)—, and R¹and R², when on non-adjacent atoms, combine to form a bridgingcycloalkyl or heterocycloalkyl.

In another embodiment, X¹ is NR³, X² is C═O, X³ is CR^(1′)R^(2′), X⁴ isCR¹R², Y¹ is N, Y³ is C, Y⁴ is CR¹, Y² is CR¹, and L is—C(O)(CR¹R²)_(m)—. In yet another embodiment, X¹ is NR, X² is C═O, X³ isCR^(1′)R^(2′), X⁴ is CR¹R², Y¹ is N, Y³ is C, Y⁴ is CR¹, Y² is CR¹, L is—C(O)(CR¹R²)_(m)—, and R¹ is H or —C₁-C₆ alkyl. In another embodiment,X¹ is NR³, X² is C═O, X³ is CR^(1′)R^(2′), X⁴ is CR¹R², Y¹ is N, Y³ isC, Y⁴ is CR¹, Y² is CR¹, L is —C(O)(CR¹R²)_(m)—, and R¹ and R², when onnon-adjacent atoms, combine to form a bridging cycloalkyl orheterocycloalkyl.

In another embodiment, X¹ is NR³, X² is C═O, X³ is CR^(1′)R^(2′), X⁴ isCR¹R², Y¹ is N, Y³ is C, Y⁴ is CR¹, Y² is CR¹, and L is—C(O)(CR¹R²)_(m)O—. In yet another embodiment, X¹ is NR³, X² is C═O, X³is CR^(1′)R^(2′), X⁴ is CR¹R², Y¹ is N, Y³ is C, Y⁴ is CR¹, Y² is CR¹, Lis —C(O)(CR¹R²)_(m)O—, and R¹ is H or —C₁-C₆ alkyl. In anotherembodiment, X¹ is NR³, X² is C═O, X³ is CR^(1′)R^(2′), X⁴ is CR¹R², Y¹is N, Y³ is C, Y⁴ is CR¹, Y² is CR¹, L is —C(O)(CR¹R²)_(m)O—, and R¹ andR², when on non-adjacent atoms, combine to form a bridging cycloalkyl orheterocycloalkyl.

In another embodiment, X¹ is O, X² is CR¹R², X³ is CR^(1′)R^(2′), X⁴ isCR¹R², Y¹ is CR¹, Y³ is CR¹, and Y⁴ is N. In yet another embodiment, X¹is O, X² is CR¹R², X³ is CR^(1′)R^(2′), X⁴ is CR¹R², Y¹ is CR¹, Y³ isCR¹, Y⁴ is N, and Y² is C. In another embodiment, X is O, X² is CR¹R²,X³ is CR^(1′)R^(2′), X⁴ is CR¹R², Y¹ is CR¹, Y³ is CR¹, Y⁴ is N, Y² isC, and L is —C(O)—. In yet another embodiment, X¹ is O, X² is CR¹R², X³is CR^(1′)R^(2′), X⁴ is CR¹R², Y¹ is CR¹, Y³ is CR¹, Y⁴ is N, Y² is C, Lis —C(O)—, and R¹ is H or —C₁-C₆ alkyl. In another embodiment, X¹ is O,X² is CR¹R², X³ is CR^(1′)R^(2′), X⁴ is CR¹R², Y¹ is CR¹, Y³ is CR¹, Y⁴is N, Y² is C, L is —C(O)—, and R¹ and R², when on non-adjacent atoms,combine to form a bridging cycloalkyl or heterocycloalkyl.

In another embodiment, X¹ is O, X² is CR¹R², X³ is CR^(1′)R^(2′), X⁴ isCR¹R², Y¹ is CR¹, Y³ is CR¹, Y⁴ is N, Y² is C, and L is—C(O)(CR¹R²)_(m)—. In yet another embodiment, X¹ is O, X² is CR¹R², X³is CR^(1′)R^(2′), X⁴ is CR¹R², Y¹ is CR¹, Y³ is CR¹, Y⁴ is N, Y² is C, Lis —C(O)(CR¹R²)_(m)—, and R¹ is H or —C₁-C₆ alkyl. In anotherembodiment, X¹ is O, X² is CR¹R², X³ is CR^(1′)R^(2′), X⁴ is CR¹R², Y¹is CR¹, Y³ is CR¹, Y⁴ is N, Y² is C, L is —C(O)(CR¹R²)_(m)—, and R¹ andR², when on non-adjacent atoms, combine to form a bridging cycloalkyl orheterocycloalkyl.

In another embodiment, X¹ is O, X² is CR¹R², X³ is CR^(1′)R^(2′), X⁴ isCR¹R², Y¹ is CR¹, Y³ is CR¹, Y⁴ is N, Y² is C, and L is—C(O)(CR¹R²)_(m)O—. In yet another embodiment, X¹ is O, X² is CR¹R², X³is CR^(1′)R^(2′), X⁴ is CR¹R², Y¹ is CR¹, Y³ is CR¹, Y⁴ is N, Y² is C, Lis —C(O)(CR¹R²)_(m)O—, and R¹ is H or —C₁-C₆ alkyl. In anotherembodiment, X¹ is O, X² is CR¹R², X³ is CR¹R², X⁴ is CR¹R², Y¹ is CR¹,Y³ is CR¹, Y⁴ is N, Y² is C, L is —C(O)(CR¹R²)_(m)O—, and R¹ and R²,when on non-adjacent atoms, combine to form a bridging cycloalkyl orheterocycloalkyl.

In another embodiment, X¹ is O, X² is CR¹R², X³ is CR^(1′)R^(2′), X⁴ isCR¹R², Y¹ is CR¹, Y³ is C, and Y⁴ is N. In another embodiment, X¹ is O,X² is CR¹R², X³ is CR^(1′)R^(2′), X⁴ is CR¹R², Y is CR¹, Y³ is C, Y⁴ isN, and Y² is CR¹. In yet another embodiment, X¹ is O, X² is CR¹R², X³ isCR^(1′)R^(2′), X⁴ is CR¹R², Y¹ is CR¹, Y³ is C, Y⁴ is N, Y² is CR¹, andL is —C(O)—. In another embodiment, X¹ is O, X² is CR¹R², X³ isCR^(1′)R^(2′), X⁴ is CR¹R², Y¹ is CR¹, Y³ is C, Y⁴ is N, Y² is CR¹, L is—C(O)—, and R¹ is H or —C₁-C₆ alkyl. In another embodiment, X¹ is O, X²is CR¹R², X³ is CR^(1′)R^(2′), X⁴ is CR¹R², Y¹ is CR¹, Y³ is C, Y⁴ is N,Y² is CR¹, L is —C(O)—, and R¹ and R², when on non-adjacent atoms,combine to form a bridging cycloalkyl or heterocycloalkyl.

In yet another embodiment, X¹ is O, X² is CR¹R², X³ is CR^(1′)R^(2′), X⁴is CR¹R², Y¹ is CR¹, Y³ is C, Y⁴ is N, Y² is CR¹, and L is—C(O)(CR¹R²)_(m)—. In another embodiment, X¹ is O, X² is CR¹R², X³ isCR^(1′)R^(2′), X⁴ is CR¹R², Y¹ is CR¹, Y³ is C, Y⁴ is N, Y² is CR¹, L is—C(O)(CR¹R²)_(m)—, and R¹ is H or —C₁-C₆ alkyl. In another embodiment,X¹ is O, X² is CR¹R², X³ is CR^(1′)R^(2′), X⁴ is CR¹R², Y¹ is CR¹, Y³ isC, Y⁴ is N, Y² is CR¹, L is —C(O)(CR¹R²)_(m)—, and R¹ and R², when onnon-adjacent atoms, combine to form a bridging cycloalkyl orheterocycloalkyl.

In yet another embodiment, X¹ is O, X² is CR¹R², X³ is CR^(1′)R^(2′), X⁴is CR¹R², Y¹ is CR¹, Y³ is C, Y⁴ is N, Y² is CR¹, and L is—C(O)(CR¹R²)_(m)O—. In another embodiment, X¹ is O, X² is CR¹R², X³ isCR^(1′)R^(2′), X⁴ is CR¹R², Y¹ is CR¹, Y³ is C, Y⁴ is N, Y² is CR¹, L is—C(O)(CR¹R²)_(m)O—, and R¹ is H or —C₁-C₆ alkyl. In another embodiment,X¹ is O, X² is CR¹R², X³ is CR^(1′)R^(2′), X⁴ is CR¹R², Y¹ is CR¹, Y³ isC, Y⁴ is N, Y² is CR¹, L is —C(O)(CR¹R²)_(m)O—, and R¹ and R², when onnon-adjacent atoms, combine to form a bridging cycloalkyl orheterocycloalkyl.

In another embodiment, X¹ is NR³, X² is C═O, X³ is CR^(1′)R^(2′), X⁴ isCR¹R², Y¹ is CR¹, Y³ is CR¹, and Y⁴ is N. In yet another embodiment, X¹is NR, X² is C═O, X³ is CR^(1′)R^(2′), X⁴ is CR¹R², Y¹ is CR¹, Y³ isCR¹, Y⁴ is N, and Y² is C. In another embodiment, X¹ is NR³, X² is C═O,X³ is CR^(1′)R^(2′), X⁴ is CR¹R², Y¹ is CR¹, Y³ is CR¹, Y⁴ is N, Y² isC, and L is —C(O)—. In yet another embodiment, X¹ is NR³, X² is C═O, X³is CR^(1′)R^(2′), X⁴ is CR¹R², Y¹ is CR¹, Y³ is CR¹, Y⁴ is N, Y² is C, Lis —C(O)—, and R¹ is H or —C₁-C₆ alkyl. In another embodiment, X¹ is NR,X² is C═O, X³ is CR^(1′)R^(2′), X⁴ is CR¹R², Y¹ is CR¹, Y³ is CR¹, Y⁴ isN, Y² is C, L is —C(O)—, and R¹ and R², when on non-adjacent atoms,combine to form a bridging cycloalkyl or heterocycloalkyl.

In yet another embodiment, X¹ is NR³, X² is C═O, X³ is CR^(1′)R^(2′), X⁴is CR¹R², Y¹ is CR¹, Y³ is CR¹, Y⁴ is N, Y² is C, and L is—C(O)(CR¹R²)_(m)—. In another embodiment, X¹ is NR, X² is C═O, X³ isCR^(1′)R^(2′), X⁴ is CR¹R², Y¹ is CR¹, Y³ is CR¹, Y⁴ is N, Y² is C, L is—C(O)(CR¹R²)_(m)—, and R¹ is H or —C₁-C₆ alkyl. In another embodiment,X¹ is NR, X² is C═O, X³ is CR^(1′)R^(2′), X⁴ is CR¹R², Y¹ is CR¹, Y³ isCR¹, Y⁴ is N, Y² is C, L is —C(O)(CR¹R²)_(m)—, and R¹ and R², when onnon-adjacent atoms, combine to form a bridging cycloalkyl orheterocycloalkyl.

In yet another embodiment, X¹ is NR³, X² is C═O, X³ is CR^(1′)R^(2′), X⁴is CR¹R², Y¹ is CR¹, Y³ is CR¹, Y⁴ is N, Y² is C, and L is—C(O)(CR¹R²)_(m)O—. In another embodiment, X¹ is NR³, X² is C═O, X³ isCR^(1′)R^(2′), X⁴ is CR¹R², Y¹ is CR¹, Y³ is CR¹, Y⁴ is N, Y² is C, L is—C(O)(CR¹R²)_(m)O—, and R¹ is H or —C₁-C₆ alkyl. In another embodiment,X¹ is NR, X² is C═O, X³ is CR^(1′)R^(2′), X⁴ is CR¹R², Y¹ is CR¹, Y³ isCR¹, Y⁴ is N, Y² is C, L is —C(O)(CR¹R²)_(m)O—, and R¹ and R², when onnon-adjacent atoms, combine to form a bridging cycloalkyl orheterocycloalkyl.

In another embodiment, X¹ is NR³, X² is C═O, X³ is CR^(1′)R^(2′), X⁴ isCR¹R², Y¹ is CR¹, Y³ is C, and Y⁴ is N. In yet another embodiment, X¹ isNR, X² is C═O, X³ is CR^(1′)R^(2′), X⁴ is CR¹R², Y¹ is CR¹, Y³ is C, Y⁴is N, and Y² is CR¹. In another embodiment, X¹ is NR³, X² is C═O, X³ isCR^(1′)R^(2′), X⁴ is CR¹R², Y¹ is CR¹, Y³ is C, Y⁴ is N, Y² is CR¹, andL is —C(O)—. In yet another embodiment, X¹ is NR³, X² is C═O, X³ isCR^(1′)R^(2′), X⁴ is CR¹R², Y¹ is CR¹, Y³ is C, Y⁴ is N, Y² is CR¹, L is—C(O)—, and R¹ is H or —C₁-C₆ alkyl. In another embodiment, X¹ is NR³,X² is C═O, X³ is CR^(1′)R^(2′), X⁴ is CR¹R², Y¹ is CR¹, Y³ is C, Y⁴ isN, Y² is CR¹, L is —C(O)—, and R¹ and R², when on non-adjacent atoms,combine to form a bridging cycloalkyl or heterocycloalkyl.

In yet another embodiment, X¹ is NR³, X² is C═O, X³ is CR^(1′)R^(2′), X⁴is CR¹R², Y¹ is CR¹, Y³ is C, Y⁴ is N, Y² is CR¹, and L is—C(O)(CR¹R²)_(m)—. In another embodiment, X¹ is NR³, X² is C═O, X³ isCR^(1′)R^(2′), X⁴ is CR¹R², Y¹ is CR¹, Y³ is C, Y⁴ is N, Y² is CR¹, L is—C(O)(CR¹R²)_(m)—, and R¹ is H or —C₁-C₆ alkyl. In another embodiment,X¹ is NR³, X² is C═O, X³ is CR^(1′)R^(2′), X⁴ is CR¹R², Y¹ is CR¹, Y³ isC, Y⁴ is N, Y² is CR¹, L is —C(O)(CR¹R²)_(m)—, and R¹ and R², when onnon-adjacent atoms, combine to form a bridging cycloalkyl orheterocycloalkyl.

In yet another embodiment, X¹ is NR³, X² is C═O, X³ is CR^(1′)R^(2′), X⁴is CR¹R², Y¹ is CR¹, Y³ is C, Y⁴ is N, Y² is CR¹, and L is—C(O)(CR¹R²)_(m)O—. In another embodiment, X¹ is NR³, X² is C═O, X³ isCR^(1′)R^(2′), X⁴ is CR¹R², Y¹ is CR¹, Y³ is C, Y⁴ is N, Y² is CR¹, L is—C(O)(CR¹R²)_(m)O—, and R¹ is H or —C₁-C₆ alkyl. In another embodiment,X¹ is NR³, X² is C═O, X³ is CR^(1′)R^(2′), X⁴ is CR¹R², Y¹ is CR¹, Y³ isC, Y⁴ is N, Y² is CR¹, L is —C(O)(CR¹R²)_(m)O—, and R¹ and R², when onnon-adjacent atoms, combine to form a bridging cycloalkyl orheterocycloalkyl.

In another embodiment, X¹ is O, X² is CR¹R², X³ is CR^(1′)R^(2′), X⁴ isCR¹R², Y¹ is N, Y³ is CR¹, and Y⁴ is N. In yet another embodiment, X¹ isO, X² is CR¹R², X³ is CR^(1′)R^(2′), X⁴ is CR¹R², Y¹ is N, Y³ is CR¹, Y⁴is N, and Y² is C. In another embodiment, X¹ is O, X² is CR¹R², X³ isCR^(1′)R^(2′), X⁴ is CR¹R², Y¹ is N, Y³ is CR¹, Y⁴ is N, Y² is C, and Lis —C(O)—. In yet another embodiment, X¹ is O, X² is CR¹R², X³ isCR^(1′)R^(2′), X⁴ is CR¹R², Y¹ is N, Y³ is CR¹, Y⁴ is N, Y² is C, L is—C(O)—, and R¹ is H or —C₁-C₆ alkyl. In another embodiment, X¹ is O, X²is CR¹R², X³ is CR^(1′)R^(2′), X⁴ is CR¹R², Y¹ is N, Y³ is CR¹, Y⁴ is N,Y² is C, L is —C(O)—, and R¹ and R², when on non-adjacent atoms, combineto form a bridging cycloalkyl or heterocycloalkyl.

In another embodiment, X¹ is O, X² is CR¹R², X³ is CR^(1′)R^(2′), X⁴ isCR¹R², Y¹ is N, Y³ is CR¹, Y⁴ is N, Y² is C, and L is —C(O)(CR¹R²)_(m)—.In another embodiment, X¹ is O, X² is CR¹R², X³ is CR^(1′)R^(2′), X⁴ isCR¹R², Y¹ is N, Y³ is CR¹, Y⁴ is N, Y² is C, L is —C(O)(CR¹R²)_(m)—, andR is H or —C₁-C₆ alkyl. In another embodiment, X¹ is O, X² is CR¹R², X³is CR^(1′)R^(2′), X⁴ is CR¹R², Y¹ is N¹, Y³ is CR¹, Y⁴ is N, Y² is C, Lis —C(O)(CR¹R²)_(m)—, and R¹ and R², when on non-adjacent atoms, combineto form a bridging cycloalkyl or heterocycloalkyl.

In another embodiment, X¹ is O, X² is CR¹R², X³ is CR^(1′)R^(2′), X⁴ isCR¹R², Y¹ is N, Y³ is CR¹, Y⁴ is N, Y² is C, and L is—C(O)(CR¹R²)_(m)O—. In another embodiment, X¹ is O, X² is CR¹R², X³ isCR^(1′)R^(2′), X⁴ is CR¹R², Y¹ is N, Y³ is CR¹, Y⁴ is N, Y² is C, L is—C(O)(CR¹R²)_(m)O—, and R is H or —C₁-C₆ alkyl. In another embodiment,X¹ is O, X² is CR¹R², X³ is CR^(1′)R^(2′), X⁴ is CR¹R², Y¹ is N, Y³ isCR¹, Y⁴ is N, Y² is C, L is —C(O)(CR¹R²)_(m)O—, and R¹ and R², when onnon-adjacent atoms, combine to form a bridging cycloalkyl orheterocycloalkyl.

In another embodiment, X¹ is O, X² is CR¹R², X³ is CR^(1′)R^(2′), X⁴ isCR¹R², Y¹ is N, Y³ is C, and Y⁴ is N. In yet another embodiment, X¹ isO, X² is CR¹R², X³ is CR^(1′)R^(2′), X⁴ is CR¹R², Y¹ is N, Y³ is C, Y⁴is N, and Y² is CR¹. In another embodiment, X¹ is O, X² is CR¹R², X³ isCR¹R², X⁴ is CR¹R², Y¹ is N, Y³ is C, Y⁴ is N, Y² is CR¹, and L is—C(O)—. In yet another embodiment, X¹ is O, X² is CR¹R², X³ isCR^(1′)R^(2′), X⁴ is CR¹R², Y¹ is N, Y³ is C, Y⁴ is N, Y² is CR¹, L is—C(O)—, and R¹ is H or —C₁-C₆ alkyl. In another embodiment, X¹ is O, X²is CR¹R², X³ is CR^(1′)R^(2′), X⁴ is CR¹R², Y¹ is N, Y³ is C, Y⁴ is N,Y² is CR¹, L is —C(O)—, and R¹ and R², when on non-adjacent atoms,combine to form a bridging cycloalkyl or heterocycloalkyl.

In another embodiment, X¹ is O, X² is CR¹R², X³ is CR^(1′)R^(2′), X⁴ isCR¹R², Y¹ is N, Y³ is C, Y⁴ is N, Y² is CR¹, and L is —C(O)(CR¹R²)_(m)—.In another embodiment, X¹ is O, X² is CR¹R², X³ is CR^(1′)R^(2′), X⁴ isCR¹R², Y¹ is N, Y³ is C, Y⁴ is N, Y² is CR¹, L is —C(O)(CR¹R²)_(m)—, andR¹ is H or —C₁-C₆ alkyl. In another embodiment, X¹ is O, X² is CR¹R², X³is CR^(1′)R^(2′), X⁴ is CR¹R², Y¹ is N¹, Y³ is C, Y⁴ is N, Y² is CR¹, Lis —C(O)(CR¹R²)_(m)—, and R¹ and R², when on non-adjacent atoms, combineto form a bridging cycloalkyl or heterocycloalkyl.

In another embodiment, X¹ is O, X² is CR¹R², X³ is CR^(1′)R^(2′), X⁴ isCR¹R², Y¹ is N, Y³ is C, Y⁴ is N, Y² is CR¹, and L is—C(O)(CR¹R²)_(m)O—. In another embodiment, X¹ is O, X² is CR¹R², X³ isCR^(1′)R^(2′), X⁴ is CR¹R², Y¹ is N, Y³ is C, Y⁴ is N, Y² is CR¹, L is—C(O)(CR¹R²)_(m)O—, and R¹ is H or —C₁-C₆ alkyl. In another embodiment,X¹ is O, X² is CR¹R², X³ is CR^(1′)R^(2′), X⁴ is CR¹R², Y¹ is N, Y³ isC, Y⁴ is N, Y² is CR¹, L is —C(O)(CR¹R²)_(m)O—, and R¹ and R², when onnon-adjacent atoms, combine to form a bridging cycloalkyl orheterocycloalkyl.

In another embodiment, X¹ is NR³, X² is C═O, X³ is CR^(1′)R^(2′), X⁴ isCR¹R², Y¹ is N, Y³ is CR¹, and Y⁴ is N. In yet another embodiment, X¹ isNR³, X² is C═O, X³ is CR^(1′)R^(2′), X⁴ is CR¹R², Y¹ is N, Y³ is CR¹, Y⁴is N, and Y² is C. In yet another embodiment, X¹ is NR³, X² is C═O, X³is CR^(1′)R^(2′), X⁴ is CR¹R², Y¹ is N, Y³ is CR¹, Y⁴ is N, Y² is C, andL is —C(O)—. In another embodiment, X¹ is NR³, X² is C═O, X³ isCR^(1′)R^(2′), X⁴ is CR¹R², Y¹ is N, Y³ is CR¹, Y⁴ is N, Y² is C, L is—C(O)—, and R¹ is H or —C₁-C₆ alkyl. In another embodiment, X¹ is NR³,X² is C═O, X³ is CR^(1′)R^(2′), X⁴ is CR¹R², Y¹ is N, Y³ is CR¹, Y⁴ isN, Y² is C, L is —C(O)—, and R¹ and R², when on non-adjacent atoms,combine to form a bridging cycloalkyl or heterocycloalkyl.

In another embodiment, X¹ is NR³, X² is C═O, X³ is CR^(1′)R^(2′), X⁴ isCR¹R², Y¹ is N, Y³ is CR¹, Y⁴ is N, Y² is C, and L is —C(O)(CR¹R²)_(m)—.In another embodiment, X¹ is NR³, X² is C═O, X³ is CR^(1′)R^(2′), X⁴ isCR¹R², Y¹ is N, Y³ is CR¹, Y⁴ is N, Y² is C, L is —C(O)(CR¹R²)_(m)—, andR¹ is H or —C₁-C₆ alkyl. In another embodiment, X¹ is NR³, X² is C═O, X³is CR^(1′)R^(2′), X⁴ is CR¹R², Y¹ is N, Y³ is CR¹, Y⁴ is N, Y² is C, Lis —C(O)(CR¹R²)_(m)—, and R¹ and R², when on non-adjacent atoms, combineto form a bridging cycloalkyl or heterocycloalkyl.

In another embodiment, X¹ is NR³, X² is C═O, X³ is CR^(1′)R^(2′), X⁴ isCR¹R², Y¹ is N, Y³ is CR¹, Y⁴ is N, Y² is C, and L is—C(O)(CR¹R²)_(m)O—. In another embodiment, X¹ is NR, X² is C═O, X³ isCR^(1′)R^(2′), X⁴ is CR¹R², Y¹ is N, Y³ is CR¹, Y⁴ is N, Y² is C, L is—C(O)(CR¹R²)_(m)O—, and R¹ is H or —C₁-C₆ alkyl. In another embodiment,X¹ is NR³, X² is C═O, X³ is CR^(1′)R^(2′), X⁴ is CR¹R², Y¹ is N, Y³ isCR¹, Y⁴ is N, Y² is C, L is —C(O)(CR¹R²)_(m)O—, and R¹ and R², when onnon-adjacent atoms, combine to form a bridging cycloalkyl orheterocycloalkyl.

In another embodiment, X¹ is NR³, X² is C═O, X³ is CR^(1′)R^(2′), X⁴ isCR¹R², Y¹ is N, Y³ is C, and Y⁴ is N. In yet another embodiment, X¹ isNR³, X² is C═O, X³ is CR^(1′)R^(2′), X⁴ is CR¹R², Y¹ is N, Y³ is C, Y⁴is N, and Y² is CR¹. In yet another embodiment, X¹ is NR, X² is C═O, X³is CR^(1′)R^(2′), X⁴ is CR¹R², Y¹ is N, Y³ is C, Y⁴ is N, Y² is CR¹, andL is —C(O)—. In another embodiment, X¹ is NR³, X² is C═O, X³ isCR^(1′)R^(2′), X⁴ is CR¹R², Y¹ is N, Y³ is C, Y⁴ is N, Y² is CR¹, L is—C(O)—, and R¹ is H or —C₁-C₆ alkyl. In another embodiment, X¹ is NR³,X² is C═O, X³ is CR^(1′)R^(2′), X⁴ is CR¹R², Y¹ is N, Y³ is C, Y⁴ is N,Y² is CR¹, L is —C(O)—, and R¹ and R², when on non-adjacent atoms,combine to form a bridging cycloalkyl or heterocycloalkyl.

In another embodiment, X¹ is NR³, X² is C═O, X³ is CR^(1′)R^(2′), X⁴ isCR¹R², Y¹ is N, Y³ is C, Y⁴ is N, Y² is CR¹, and L is —C(O)(CR¹R²)_(m)—.In another embodiment, X¹ is NR³, X² is C═O, X³ is CR^(1′)R^(2′), X⁴ isCR¹R², Y¹ is N, Y³ is C, Y⁴ is N, Y² is CR¹, L is —C(O)(CR¹R²)_(m)—, andR¹ is H or —C₁-C₆ alkyl. In another embodiment, X¹ is NR³, X² is C═O, X³is CR^(1′)R^(2′), X⁴ is CR¹R², Y¹ is N, Y³ is C, Y⁴ is N, Y² is CR¹, Lis —C(O)(CR¹R²)_(m)—, and R¹ and R², when on non-adjacent atoms, combineto form a bridging cycloalkyl or heterocycloalkyl.

In another embodiment, X¹ is NR³, X² is C═O, X³ is CR^(1′)R^(2′), X⁴ isCR¹R², Y¹ is N, Y³ is C, Y⁴ is N, Y² is CR¹, and L is—C(O)(CR¹R²)_(m)O—. In another embodiment, X¹ is NR, X² is C═O, X³ isCR^(1′)R^(2′), X⁴ is CR¹R², Y¹ is N, Y³ is C, Y⁴ is N, Y² is CR¹, L is—C(O)(CR¹R²)_(m)O—, and R¹ is H or —C₁-C₆ alkyl. In another embodiment,X¹ is NR, X² is C═O, X³ is CR^(1′)R^(2′), X⁴ is CR¹R², Y¹ is N, Y³ is C,Y⁴ is N, Y² is CR¹, L is —C(O)(CR¹R²)_(m)O—, and R¹ and R², when onnon-adjacent atoms, combine to form a bridging cycloalkyl orheterocycloalkyl.

In some embodiments of Formula (I), X² is CR¹R²; R¹ is —H, or —C₁-C₆alkyl; and R² is —H, —R³, aryl, or —C₁-C₆ alkyl optionally substitutedwith one or more substituents selected from oxo, —OR³, and —NR³R⁴.

In some embodiments of Formula (I), X³ is CR^(1′)R^(2′); R^(1′) is —H,or —C₁-C₆ alkyl; and R^(2′) is —H, heterocyclyl, or —C₁-C₆ alkyloptionally substituted with one or more substituents selected fromhalogen, aryl, and —OR³.

In some embodiments of Formula (I), R¹ and R² combine with the atom towhich they are both attached to form a spirocycle. In anotherembodiment, R¹ and R² combine with the atom to which they are bothattached to form a spiroheterocycle. In another embodiment, R¹ and R²combine with the atom to which they are both attached to form aspirocycloalkenyl.

In some embodiments of Formula (I), R¹ and R², when on adjacent atoms,combine to form a heterocycle. In another embodiment, R¹ and R², when onadjacent atoms, combine to form a cycloalkyl. In yet another embodiment,R¹ and R², when on adjacent atoms, combine to form a cycloalkenyl. Inanother embodiment, R¹ and R², when on adjacent atoms, combine to forman aryl. In yet another embodiment, R¹ and R², when on adjacent atoms,combine to form a heteroaryl containing 1 to 5 heteroatoms selected fromthe group consisting of N, S, P, and O.

In some embodiments of Formula (I), R¹ and R², when on non-adjacentatoms, combine to form a bridging cycloalkyl. In another embodiment, R¹and R², when on non-adjacent atoms, combine to form a bridgingcycloalkenyl. In yet another embodiment, R and R²-when on non-adjacentatoms, combine to form a heterocycloalkyl.

In some embodiments of Formula (I), R^(1′) and R^(2′) combine with thecarbon atom to which they are both attached to form a spirocycle. Inanother embodiment, R^(1′) and R^(2′) combine with the carbon atom towhich they are both attached to form a spiroheterocycle. In yet anotherembodiment, R^(1′) and R^(2′) combine with the carbon atom to which theyare both attached to form a spirocycloalkenyl.

In some embodiments of Formula (I), R^(1′) and R^(2′) combine with R¹ orR² on adjacent atoms to form a heterocycle. In another embodiment,R^(1′) and R^(2′) combine with R¹ or R² on adjacent atoms to form acycloalkyl. In yet another embodiment, R^(1′) and R^(2′) combine with R¹or R² on adjacent atoms to form an aryl. In another embodiment, R^(1′)and R^(2′) combine with R¹ or R² on adjacent atoms to form a heteroarylcontaining 1-5 heteroatoms selected from the group consisting of N, S,P, or O. In another embodiment, R^(1′) and R^(2′) combine with R¹ or R²on adjacent atoms to form a cycloalkenyl.

In some embodiments of Formula (I), R^(1′) and R^(2′) combine with R¹ orR² on non-adjacent atoms, to form a bridging cycloalkyl. In anotherembodiment, R^(1′) and R^(2′) combine with R¹ or R² on non-adjacentatoms, to form a bridging heterocycloalkyl.

In some embodiments of Formula (I), n is 1 to 6. In another embodiment,n is 0 to 5. In yet another embodiment, n is 0 to 4. In yet anotherembodiment, n is 1 to 4. In another embodiment, n is 0 to 3. In yetanother embodiment, n is 0 to 2. In yet another embodiment, n is 0 or 1.In another embodiment, n is 1 or 2.

In some embodiments of Formula (I), m is 1 to 6. In another embodiment,m is 1 to 5. In yet another embodiment, m is 1 to 4. In yet anotherembodiment, m is 1 to 3. In another embodiment, m is 1 or 2. In yetanother embodiment, m is 2 or 3. In yet another embodiment, m is 2 to 4.

In some embodiments of Formula (I), X⁴, X², and X¹ are not allsimultaneously CR¹R².

In some embodiments of Formula (I), X¹ is O, X² is CR¹R², and X⁴ isCR¹R². In another embodiment, X² is C═O, X⁴ is C═O, and X is CR¹R². Inyet another embodiment, X¹ is NR³, X² is C═O, and X⁴ is CR¹R².

In an illustrative embodiment, the compound of Formula I is:

-   4-(2,2-dimethyltetrahydro-2H-pyran-4-carbonyl)-N-hydroxy-2,3,4,5-tetrahydrobenzo[f][1,4]oxazepine-8-carboxamide;-   N-hydroxy-4-(2-methyl-2-(pyridin-2-yl)propanoyl)-2,3,4,5-tetrahydrobenzo[f][1,4]oxazepine-8-carboxamide;-   4-(2,6-dimethylbenzoyl)-N-hydroxy-2,3,4,5-tetrahydrobenzo[f][1,4]oxazepine-8-carboxamide-   N-hydroxy-4-(3-methoxy-2,2-dimethylpropanoyl)-2,3,4,5-tetrahydrobenzo[f][1,4]oxazepine-8-carboxamide;-   4-(8-oxabicyclo[3.2.1]octane-3-carbonyl)-N-hydroxy-2,3,4,5-tetrahydrobenzo[f][1,4]oxazepine-8-carboxamide;-   N-hydroxy-4-(3-(propylamino)benzo[b]thiophene-2-carbonyl)-2,3,4,5-tetrahydrobenzo[f][1,4]oxazepine-8-carboxamide;-   4-(3-(dimethylamino)benzo[b]thiophene-2-carbonyl)-N-hydroxy-2,3,4,5-tetrahydrobenzo[f][1,4]oxazepine-8-carboxamide;-   tert-butyl    7-(8-(hydroxycarbamoyl)-2,3,4,5-tetrahydrobenzo[f][1,4]oxazepine-4-carbonyl)-5-oxa-2-azaspiro[3.4]octane-2-carboxylate;-   tert-butyl    7-(8-(hydroxycarbamoyl)-2,3,4,5-tetrahydrobenzo[f][1,4]oxazepine-4-carbonyl)-5-thia-2-azaspiro[3.4]octane-2-carboxylate    5,5-dioxide;-   (S)—N-hydroxy-4-(tetrahydro-2H-pyran-3-carbonyl)-2,3,4,5-tetrahydrobenzo[f][1,4]oxazepine-8-carboxamide;-   (R)—N-hydroxy-4-(tetrahydro-2H-pyran-3-carbonyl)-2,3,4,5-tetrahydrobenzo[f][1,4]oxazepine-8-carboxamide;-   (R)—N-hydroxy-4-(tetrahydrofuran-3-carbonyl)-2,3,4,5-tetrahydrobenzo[f][1,4]oxazepine-8-carboxamide;-   (S)—N-hydroxy-4-(tetrahydrofuran-3-carbonyl)-2,3,4,5-tetrahydrobenzo[f][1,4]oxazepine-8-carboxamide;-   4-benzoyl-N-hydroxy-2,3,4,5-tetrahydrobenzo[f][1,4]oxazepine-8-carboxamide;-   N-hydroxy-4-pivaloyl-2,3,4,5-tetrahydrobenzo[f][1,4]oxazepine-8-carboxamide;-   4-acetyl-N-hydroxy-2,3,4,5-tetrahydrobenzo[f][1,4]oxazepine-8-carboxamide;-   4-formyl-N-hydroxy-2,3,4,5-tetrahydrobenzo[f][1,4]oxazepine-8-carboxamide;-   tert-butyl    3-(8-(hydroxycarbamoyl)-2,3,4,5-tetrahydrobenzo[f][1,4]oxazepine-4-carbonyl)-3H-spiro[isobenzofuran-1,4′-piperidine]-1′-carboxylate;-   N-hydroxy-4-(8-azaspiro[4.5]decane-2-carbonyl)-2,3,4,5-tetrahydrobenzo[f][1,4]oxazepine-8-carboxamide;-   tert-butyl    8-(8-(hydroxycarbamoyl)-2,3,4,5-tetrahydrobenzo[f][1,4]oxazepine-4-carbonyl)-2-azaspiro[4.5]decane-2-carboxylate;-   N-hydroxy-4-(2-azaspiro[4.5]decane-8-carbonyl)-2,3,4,5-tetrahydrobenzo[f][1,4]oxazepine-8-carboxamide;-   tert-butyl    6-(8-(hydroxycarbamoyl)-2,3,4,5-tetrahydrobenzo[f][1,4]oxazepine-4-carbonyl)-2-azaspiro[4.4]nonane-2-carboxylate;-   N-hydroxy-4-(2-azaspiro[4.4]nonane-6-carbonyl)-2,3,4,5-tetrahydrobenzo[f][1,4]oxazepine-8-carboxamide;-   N-hydroxy-4-(3H-spiro[isobenzofuran-1,4′-piperidine]-3-carbonyl)-2,3,4,5-tetrahydrobenzo[f][1,4]oxazepine-8-carboxamide;-   tert-butyl    2-(8-(hydroxycarbamoyl)-2,3,4,5-tetrahydrobenzo[f][1,4]oxazepine-4-carbonyl)-2H-spiro[benzofuran-3,4′-piperidine]-1′-carboxylate;-   N-hydroxy-4-(2H-spiro[benzofuran-3,4′-piperidine]-2-carbonyl)-2,3,4,5-tetrahydrobenzo[f][1,4]oxazepine-8-carboxamide;-   tert-butyl    3-(8-(hydroxycarbamoyl)-2,3,4,5-tetrahydrobenzo[f][1,4]oxazepine-4-carbonyl)-2,3-dihydrospiro[indene-1,4′-piperidine]-1′-carboxylate;-   4-(2,3-dihydrospiro[indene-1,4′-piperidine]-3-carbonyl)-N-hydroxy-2,3,4,5-tetrahydrobenzo[f][1,4]oxazepine-8-carboxamide;-   tert-butyl    9-(8-(hydroxycarbamoyl)-2,3,4,5-tetrahydrobenzo[f][1,4]oxazepine-4-carbonyl)-3-azaspiro[5.5]undecane-3-carboxylate;-   tert-butyl    2-(8-(hydroxycarbamoyl)-2,3,4,5-tetrahydrobenzo[f][1,4]oxazepine-4-carbonyl)-8-azaspiro[4.5]decane-8-carboxylate;-   N-hydroxy-4-(3-azaspiro[5.5]undecane-9-carbonyl)-2,3,4,5-tetrahydrobenzo[f][1,4]oxazepine-8-carboxamide;-   N-hydroxy-4-(5-azaspiro[2.5]octane-1-carbonyl)-2,3,4,5-tetrahydrobenzo[f][1,4]oxazepine-8-carboxamide;-   N-hydroxy-4-(5-azaspiro[2.4]heptane-1-carbonyl)-2,3,4,5-tetrahydrobenzo[f][1,4]oxazepine-8-carboxamide;-   N-hydroxy-4-(6-azaspiro[2.5]octane-1-carbonyl)-2,3,4,5-tetrahydrobenzo[f][1,4]oxazepine-8-carboxamide;-   tert-butyl    1-(8-(hydroxycarbamoyl)-2,3,4,5-tetrahydrobenzo[f][1,4]oxazepine-4-carbonyl)-6-azaspiro[2.5]octane-6-carboxylate;-   (R)—N-hydroxy-2-methyl-4-(1-methylcyclobutane-1-carbonyl)-2,3,4,5-tetrahydrobenzo[f][1,4]oxazepine-8-carboxamide;-   (R)-4-formyl-N-hydroxy-2-methyl-2,3,4,5-tetrahydrobenzo[f][1,4]oxazepine-8-carboxamide;-   (R)-4-acetyl-N-hydroxy-2-methyl-2,3,4,5-tetrahydrobenzo[f][1,4]oxazepine-8-carboxamide;-   (S)-4-acetyl-N-hydroxy-2-methyl-2,3,4,5-tetrahydrobenzo[f][1,4]oxazepine-8-carboxamide;-   (S)—N-hydroxy-2-methyl-4-(1-methylcyclobutane-1-carbonyl)-2,3,4,5-tetrahydrobenzo[f][1,4]oxazepine-8-carboxamide;-   (S)-4-formyl-N-hydroxy-2-methyl-2,3,4,5-tetrahydrobenzo[f][1,4]oxazepine-8-carboxamide;-   N-hydroxy-3,3-dimethyl-4-(1-methylcyclobutane-1-carbonyl)-2,3,4,5-tetrahydrobenzo[f][1,4]oxazepine-8-carboxamide;-   4-acetyl-N-hydroxy-3,3-dimethyl-2,3,4,5-tetrahydrobenzo[f][1,4]oxazepine-8-carboxamide;-   (R)-4-acetyl-N-hydroxy-3-isopropyl-2,3,4,5-tetrahydrobenzo[f][1,4]oxazepine-8-carboxamide;-   (R)—N-hydroxy-3-isopropyl-4-(1-methylcyclobutane-1-carbonyl)-2,3,4,5-tetrahydrobenzo[f][1,4]oxazepine-8-carboxamide;-   (S)-4-acetyl-N-hydroxy-3-isopropyl-2,3,4,5-tetrahydrobenzo[f][1,4]oxazepine-8-carboxamide;-   (S)—N-hydroxy-3-isopropyl-4-(1-methylcyclobutane-1-carbonyl)-2,3,4,5-tetrahydrobenzo[f][1,4]oxazepine-8-carboxamide;-   (R)-4-formyl-N-hydroxy-3-methyl-2,3,4,5-tetrahydrobenzo[f][1,4]oxazepine-8-carboxamide;-   (R)—N-hydroxy-3-methyl-4-(1-methylcyclobutane-1-carbonyl)-2,3,4,5-tetrahydrobenzo[f][1,4]oxazepine-8-carboxamide;-   (R)-4-acetyl-N-hydroxy-3-methyl-2,3,4,5-tetrahydrobenzo[f][1,4]oxazepine-8-carboxamide;-   (S)—N-hydroxy-3-methyl-4-(1-methylcyclobutane-1-carbonyl)-2,3,4,5-tetrahydrobenzo[f][1,4]oxazepine-8-carboxamide;-   (S)-4-(1,1-dioxidotetrahydro-2H-thiopyran-4-carbonyl)-N-hydroxy-3-methyl-2,3,4,5-tetrahydrobenzo[f][1,4]oxazepine-8-carboxamide;-   (S)—N-hydroxy-4-(1-methoxycyclopentane-1-carbonyl)-3-methyl-2,3,4,5-tetrahydrobenzo[f][1,4]oxazepine-8-carboxamide;-   (3S)-4-(1,1-dioxidotetrahydrothiophene-3-carbonyl)-N-hydroxy-3-methyl-2,3,4,5-tetrahydrobenzo[f][1,4]oxazepine-8-carboxamide;-   (S)—N-hydroxy-4-(1-methoxycyclobutane-1-carbonyl)-3-methyl-2,3,4,5-tetrahydrobenzo[f][1,4]oxazepine-8-carboxamide;-   (S)—N-hydroxy-3-methyl-4-(3-methyloxetane-3-carbonyl)-2,3,4,5-tetrahydrobenzo[f][1,4]oxazepine-8-carboxamide;-   (S)—N-hydroxy-3-methyl-4-(oxetane-3-carbonyl)-2,3,4,5-tetrahydrobenzo[f][1,4]oxazepine-8-carboxamide;-   (S)-4-(1,1-dioxidothietane-3-carbonyl)-N-hydroxy-3-methyl-2,3,4,5-tetrahydrobenzo[f][1,4]oxazepine-8-carboxamide;-   (S)—N-hydroxy-4-(1-methoxycyclopropane-1-carbonyl)-3-methyl-2,3,4,5-tetrahydrobenzo[f][1,4]oxazepine-8-carboxamide;-   (S)—N-hydroxy-3-methyl-4-(tetrahydro-2H-pyran-4-carbonyl)-2,3,4,5-tetrahydrobenzo[f][1,4]oxazepine-8-carboxamide;-   (S)—N-hydroxy-4-(2-methoxy-2-methylpropanoyl)-3-methyl-2,3,4,5-tetrahydrobenzo[f][1,4]oxazepine-8-carboxamide;-   (S)—N-hydroxy-3-methyl-4-(4-methyltetrahydro-2H-pyran-4-carbonyl)-2,3,4,5-tetrahydrobenzo[f][1,4]oxazepine-8-carboxamide;-   (S)—N-hydroxy-4-(4-methoxytetrahydro-2H-pyran-4-carbonyl)-3-methyl-2,3,4,5-tetrahydrobenzo[f][1,4]oxazepine-8-carboxamide;-   (S)—N-hydroxy-4-(1-methoxycyclohexane-1-carbonyl)-3-methyl-2,3,4,5-tetrahydrobenzo[f][1,4]oxazepine-8-carboxamide;-   (3S)-4-(8-oxabicyclo[3.2.1]octane-3-carbonyl)-N-hydroxy-3-methyl-2,3,4,5-tetrahydrobenzo[f][1,4]oxazepine-8-carboxamide;-   (3S)-4-(2,6-dimethyltetrahydro-2H-pyran-4-carbonyl)-N-hydroxy-3-methyl-2,3,4,5-tetrahydrobenzo[f][1,4]oxazepine-8-carboxamide;-   (S)-4-formyl-N-hydroxy-3-methyl-2,3,4,5-tetrahydrobenzo[f][1,4]oxazepine-8-carboxamide;-   (S)-4-acetyl-N-hydroxy-3-methyl-2,3,4,5-tetrahydrobenzo[f][1,4]oxazepine-8-carboxamide;-   (S)-4-(1-acetylpiperidine-4-carbonyl)-N-hydroxy-3-methyl-2,3,4,5-tetrahydrobenzo[f][1,4]oxazepine-8-carboxamide;-   (3S)-4-(1-acetylpyrrolidine-3-carbonyl)-N-hydroxy-3-methyl-2,3,4,5-tetrahydrobenzo[f][1,4]oxazepine-8-carboxamide;-   (R)—N-hydroxy-5-methyl-4-(1-methylcyclobutane-1-carbonyl)-2,3,4,5-tetrahydrobenzo[f][1,4]oxazepine-7-carboxamide;-   (S)—N-hydroxy-5-methyl-4-(1-methylcyclobutane-1-carbonyl)-2,3,4,5-tetrahydrobenzo[f][1,4]oxazepine-7-carboxamide;-   (R)—N-hydroxy-5-methyl-4-(tetrahydro-2H-pyran-4-carbonyl)-2,3,4,5-tetrahydrobenzo[f][1,4]oxazepine-7-carboxamide;-   (S)—N-hydroxy-5-methyl-4-(tetrahydro-2H-pyran-4-carbonyl)-2,3,4,5-tetrahydrobenzo[f][1,4]oxazepine-7-carboxamide;-   4-(cyclohexanecarbonyl)-N-hydroxy-2,3,4,5-tetrahydropyrido[2,3-f][1,4]oxazepine-8-carboxamide;-   4-(cyclohexanecarbonyl)-N-hydroxy-2,3,4,5-tetrahydropyrido[3,2-f][1,4]oxazepine-8-carboxamide;-   N-hydroxy-4-(2-(4-methoxyphenyl)acetyl)-2-oxo-2,3,4,5-tetrahydro-1H-benzo[e][1,4]diazepine-7-carboxamide;-   N-hydroxy-4-(4-methoxybenzoyl)-2-oxo-2,3,4,5-tetrahydro-1H-benzo[e][1,4]diazepine-7-carboxamide;-   4-(cyclohexanecarbonyl)-N-hydroxy-2-oxo-2,3,4,5-tetrahydro-1H-benzo[e][1,4]diazepine-7-carboxamide;-   4-(cyclohexanecarbonyl)-N-hydroxy-2,3,4,5-tetrahydrobenzo[f][1,4]oxazepine-8-carboxamide;-   N-hydroxy-4-(4-methoxybenzoyl)-2,3,4,5-tetrahydrobenzo[f][1,4]oxazepine-8-carboxamide;-   N-hydroxy-4-(4-methoxybenzoyl)-2,3,4,5-tetrahydrobenzo[f][1,4]oxazepine-7-carboxamide;-   N-hydroxy-4-(2-(4-methoxyphenyl)acetyl)-2,3,4,5-tetrahydrobenzo[f][1,4]oxazepine-8-carboxamide;-   N-hydroxy-4-(2-(4-methoxyphenyl)acetyl)-2,3,4,5-tetrahydrobenzo[f][1,4]oxazepine-7-carboxamide;-   N-hydroxy-4-(4-(trifluoromethyl)benzoyl)-2,3,4,5-tetrahydrobenzo[f][1,4]oxazepine-8-carboxamide;-   4-(benzo[d][1,3]dioxole-5-carbonyl)-N-hydroxy-2,3,4,5-tetrahydrobenzo[f][1,4]oxazepine-8-carboxamide;-   N-hydroxy-4-(1H-indole-5-carbonyl)-2,3,4,5-tetrahydrobenzo[f][1,4]oxazepine-8-carboxamide;-   N-hydroxy-4-(1-phenylcyclopropane-1-carbonyl)-2,3,4,5-tetrahydrobenzo[f][1,4]oxazepine-8-carboxamide;-   N-hydroxy-4-(2-(4-methoxyphenoxy)acetyl)-2,3,4,5-tetrahydrobenzo[f][1,4]oxazepine-8-carboxamide;-   N-hydroxy-4-(3-methoxybenzoyl)-2,3,4,5-tetrahydrobenzo[f][1,4]oxazepine-8-carboxamide;-   4-(4-(difluoromethoxy)benzoyl)-N-hydroxy-2,3,4,5-tetrahydrobenzo[f][1,4]oxazepine-8-carboxamide;-   N-hydroxy-4-(4-phenoxybenzoyl)-2,3,4,5-tetrahydrobenzo[f][1,4]oxazepine-8-carboxamide;-   4-(2,3-dihydrobenzofuran-5-carbonyl)-N-hydroxy-2,3,4,5-tetrahydrobenzo[f][1,4]oxazepine-8-carboxamide;-   4-(2,4-dimethoxybenzoyl)-N-hydroxy-2,3,4,5-tetrahydrobenzo[f][1,4]oxazepine-8-carboxamide;-   N-hydroxy-4-(1-methyl-6-oxo-1,6-dihydropyridine-3-carbonyl)-2,3,4,5-tetrahydrobenzo[f][1,4]oxazepine-8-carboxamide;-   N-hydroxy-4-(tetrahydro-2H-pyran-4-carbonyl)-2,3,4,5-tetrahydrobenzo[f][1,4]oxazepine-8-carboxamide;-   4-(benzofuran-5-carbonyl)-N-hydroxy-2,3,4,5-tetrahydrobenzo[f][1,4]oxazepine-8-carboxamide;-   N-hydroxy-4-(4-morpholinobenzoyl)-2,3,4,5-tetrahydrobenzo[f][1,4]oxazepine-8-carboxamide;-   4-(cyclopropanecarbonyl)-N-hydroxy-2,3,4,5-tetrahydrobenzo[f][1,4]oxazepine-8-carboxamide;-   4-(cyclobutanecarbonyl)-N-hydroxy-2,3,4,5-tetrahydrobenzo[f][1,4]oxazepine-8-carboxamide;-   N-hydroxy-4-(1-methylcyclohexane-1-carbonyl)-2,3,4,5-tetrahydrobenzo[f][1,4]oxazepine-8-carboxamide;-   N-hydroxy-4-(2-phenylbutanoyl)-2,3,4,5-tetrahydrobenzo[f][1,4]oxazepine-8-carboxamide;-   4-(2-cyclohexyl-2-phenylacetyl)-N-hydroxy-2,3,4,5-tetrahydrobenzo[f][1,4]oxazepine-8-carboxamide;-   4-(bicyclo[4.2.0]octa-1(6),2,4-triene-7-carbonyl)-N-hydroxy-2,3,4,5-tetrahydrobenzo[f][1,4]oxazepine-8-carboxamide;-   N-hydroxy-4-(1-methylcyclobutane-1-carbonyl)-2,3,4,5-tetrahydrobenzo[f][1,4]oxazepine-8-carboxamide;-   (S)—N-hydroxy-4-(2-phenylpropanoyl)-2,3,4,5-tetrahydrobenzo[f][1,4]oxazepine-8-carboxamide;-   (R)—N-hydroxy-4-(2-phenylpropanoyl)-2,3,4,5-tetrahydrobenzo[f][1,4]oxazepine-8-carboxamide;-   N-hydroxy-4-(3-phenylpropanoyl)-2,3,4,5-tetrahydrobenzo[f][1,4]oxazepine-8-carboxamide;-   N-hydroxy-4-(2-(5-methoxy-1H-indol-3-yl)acetyl)-2,3,4,5-tetrahydrobenzo[f][1,4]oxazepine-8-carboxamide;-   4-(2-(1,1-dioxidothiomorpholino)propanoyl)-N-hydroxy-2,3,4,5-tetrahydrobenzo[f][1,4]oxazepine-8-carboxamide;-   N-hydroxy-4-(2-(4-(trifluoromethyl)phenyl)acetyl)-2,3,4,5-tetrahydrobenzo[f][1,4]oxazepine-8-carboxamide;-   N-hydroxy-4-(2-(2-phenoxyphenyl)acetyl)-2,3,4,5-tetrahydrobenzo[f][1,4]oxazepine-8-carboxamide;-   4-(2-(3-chlorophenoxy)acetyl)-N-hydroxy-2,3,4,5-tetrahydrobenzo[f][1,4]oxazepine-8-carboxamide;-   N-hydroxy-4-(4,4,4-trifluorobutanoyl)-2,3,4,5-tetrahydrobenzo[f][1,4]oxazepine-8-carboxamide;-   4-(cyclopentanecarbonyl)-N-hydroxy-2,3,4,5-tetrahydrobenzo[f][1,4]oxazepine-8-carboxamide;-   N-hydroxy-4-isobutyryl-2,3,4,5-tetrahydrobenzo[f][1,4]oxazepine-8-carboxamide;-   N-hydroxy-4-(2-(1-(methylsulfonyl)piperidin-4-yl)acetyl)-2,3,4,5-tetrahydrobenzo[f][1,4]oxazepine-8-carboxamide;-   N-hydroxy-4-(2-(2-methylthiazol-4-yl)acetyl)-2,3,4,5-tetrahydrobenzo[f][1,4]oxazepine-8-carboxamide;-   4-(2-(1,1-dioxidothiomorpholino)acetyl)-N-hydroxy-2,3,4,5-tetrahydrobenzo[f][1,4]oxazepine-8-carboxamide;-   N-hydroxy-4-(2-morpholinoacetyl)-2,3,4,5-tetrahydrobenzo[f][1,4]oxazepine-8-carboxamide;-   N-hydroxy-4-(2-methoxy-2-phenylacetyl)-2,3,4,5-tetrahydrobenzo[f][1,4]oxazepine-8-carboxamide;-   4-(2-(4-fluorophenyl)propanoyl)-N-hydroxy-2,3,4,5-tetrahydrobenzo[f][1,4]oxazepine-8-carboxamide;-   4-(2,3-dihydro-1H-indene-2-carbonyl)-N-hydroxy-2,3,4,5-tetrahydrobenzo[f][1,4]oxazepine-8-carboxamide;-   N-hydroxy-4-(3-phenylbutanoyl)-2,3,4,5-tetrahydrobenzo[f][1,4]oxazepine-8-carboxamide;-   N-hydroxy-4-(2-phenoxypropanoyl)-2,3,4,5-tetrahydrobenzo[f][1,4]oxazepine-8-carboxamide;-   4-(1-acetylpiperidine-3-carbonyl)-N-hydroxy-2,3,4,5-tetrahydrobenzo[f][1,4]oxazepine-8-carboxamide;-   N-hydroxy-4-(2-phenoxybutanoyl)-2,3,4,5-tetrahydrobenzo[f][1,4]oxazepine-8-carboxamide;-   N-hydroxy-4-(2-phenylcyclopropane-1-carbonyl)-2,3,4,5-tetrahydrobenzo[f][1,4]oxazepine-8-carboxamide;-   N-hydroxy-4-(2-(2-oxo-3-(trifluoromethyl)pyridin-1(2H)-yl)acetyl)-2,3,4,5-tetrahydrobenzo[f][1,4]oxazepine-8-carboxamide;-   N-hydroxy-4-(2-isobutoxyacetyl)-2,3,4,5-tetrahydrobenzo[f][1,4]oxazepine-8-carboxamide;-   4-(4,4-difluorocyclohexane-1-carbonyl)-N-hydroxy-2,3,4,5-tetrahydrobenzo[f][1,4]oxazepine-8-carboxamide;-   N-hydroxy-4-(N-methyl-N-(methylsulfonyl)glycyl)-2,3,4,5-tetrahydrobenzo[f][1,4]oxazepine-8-carboxamide;-   (S)-4-(2,2-dimethylcyclopropane-1-carbonyl)-N-hydroxy-2,3,4,5-tetrahydrobenzo[f][1,4]oxazepine-8-carboxamide;-   4-(3,3-difluorocyclobutane-1-carbonyl)-N-hydroxy-2,3,4,5-tetrahydrobenzo[f][1,4]oxazepine-8-carboxamide;-   4-(2-cyclopropylacetyl)-N-hydroxy-2,3,4,5-tetrahydrobenzo[f][1,4]oxazepine-8-carboxamide;-   N-hydroxy-4-(3-hydroxypropanoyl)-2,3,4,5-tetrahydrobenzo[f][1,4]oxazepine-8-carboxamide;-   N-hydroxy-4-(1-hydroxycyclopropane-1-carbonyl)-2,3,4,5-tetrahydrobenzo[f][1,4]oxazepine-8-carboxamide;-   N-hydroxy-4-(2-hydroxy-2-methylpropanoyl)-2,3,4,5-tetrahydrobenzo[f][1,4]oxazepine-8-carboxamide;-   4-(2-cyclopentyl-2-hydroxy-2-phenylacetyl)-N-hydroxy-2,3,4,5-tetrahydrobenzo[f][1,4]oxazepine-8-carboxamide;-   N-hydroxy-4-(2-(3-methoxyphenyl)-2-methylpropanoyl)-2,3,4,5-tetrahydrobenzo[f][1,4]oxazepine-8-carboxamide;-   4-(2-(4-chloro-1H-pyrazol-1-yl)-2-methylpropanoyl)-N-hydroxy-2,3,4,5-tetrahydrobenzo[f][1,4]oxazepine-8-carboxamide;-   4-(2-cyclohexyl-2-methylpropanoyl)-N-hydroxy-2,3,4,5-tetrahydrobenzo[f][1,4]oxazepine-8-carboxamide;-   4-(2-(3,4-dimethoxyphenyl)-2-methylpropanoyl)-N-hydroxy-2,3,4,5-tetrahydrobenzo[f][1,4]oxazepine-8-carboxamide;-   4-(2-([1,1′-biphenyl]-4-yl)-2-methylpropanoyl)-N-hydroxy-2,3,4,5-tetrahydrobenzo[f][1,4]oxazepine-8-carboxamide;-   N-hydroxy-4-(2-methyl-2-(3-methyl-1H-pyrazol-1-yl)propanoyl)-2,3,4,5-tetrahydrobenzo[f][1,4]oxazepine-8-carboxamide;-   N-hydroxy-4-(2-methyl-2-(naphthalen-2-yl)propanoyl)-2,3,4,5-tetrahydrobenzo[f][1,4]oxazepine-8-carboxamide;-   N-hydroxy-4-(2-(2-methoxyphenyl)-2-methylpropanoyl)-2,3,4,5-tetrahydrobenzo[f][1,4]oxazepine-8-carboxamide;-   N-hydroxy-4-(2-methyl-2-(pyridin-3-yl)propanoyl)-2,3,4,5-tetrahydrobenzo[f][1,4]oxazepine-8-carboxamide;-   4-(2-(4-fluorophenyl)-2-methylpropanoyl)-N-hydroxy-2,3,4,5-tetrahydrobenzo[f][1,4]oxazepine-8-carboxamide;-   4-(2-(2,3-dihydrobenzo[b][1,4]dioxin-6-yl)-2-methylpropanoyl)-N-hydroxy-2,3,4,5-tetrahydrobenzo[f][1,4]oxazepine-8-carboxamide;-   N-hydroxy-4-(2-methyl-2-(thiophen-2-yl)propanoyl)-2,3,4,5-tetrahydrobenzo[f][1,4]oxazepine-8-carboxamide;-   N-hydroxy-4-(3-(4-methoxyphenyl)-2-phenylpropanoyl)-2,3,4,5-tetrahydrobenzo[f][1,4]oxazepine-8-carboxamide;-   N-hydroxy-4-(2-(5-methyl-1H-tetrazol-1-yl)-2-phenylacetyl)-2,3,4,5-tetrahydrobenzo[f][1,4]oxazepine-8-carboxamide;-   N-hydroxy-4-(2-phenyl-2-(1H-tetrazol-1-yl)acetyl)-2,3,4,5-tetrahydrobenzo[f][1,4]oxazepine-8-carboxamide;-   N-hydroxy-4-(2-phenyl-2-((tetrahydro-2H-pyran-4-yl)oxy)acetyl)-2,3,4,5-tetrahydrobenzo[f][1,4]oxazepine-8-carboxamide;-   N-hydroxy-4-(2-hydroxy-3-methyl-2-phenylbutanoyl)-2,3,4,5-tetrahydrobenzo[f][1,4]oxazepine-8-carboxamide;-   N-hydroxy-4-(2-(4-hydroxypiperidin-1-yl)-2-phenylacetyl)-2,3,4,5-tetrahydrobenzo[f][1,4]oxazepine-8-carboxamide;-   N-hydroxy-4-(2-phenyl-2-(2,2,2-trifluoroethoxy)acetyl)-2,3,4,5-tetrahydrobenzo[f][1,4]oxazepine-8-carboxamide;-   4-(2-(tert-butoxy)-2-phenylacetyl)-N-hydroxy-2,3,4,5-tetrahydrobenzo[f][1,4]oxazepine-8-carboxamide;-   N-hydroxy-4-(2-phenyl-2-(1H-pyrazol-1-yl)acetyl)-2,3,4,5-tetrahydrobenzo[f][1,4]oxazepine-8-carboxamide;-   N-hydroxy-4-(2-methoxy-2-phenylpropanoyl)-2,3,4,5-tetrahydrobenzo[f][1,4]oxazepine-8-carboxamide;-   N-hydroxy-4-(2-phenoxy-2-phenylacetyl)-2,3,4,5-tetrahydrobenzo[f][1,4]oxazepine-8-carboxamide;-   N-hydroxy-4-(2-(2-oxopiperidin-1-yl)-2-phenylacetyl)-2,3,4,5-tetrahydrobenzo[f][1,4]oxazepine-8-carboxamide;-   N-hydroxy-4-(2-methyl-2-phenylpropanoyl)-2,3,4,5-tetrahydrobenzo[f][1,4]oxazepine-8-carboxamide;-   N-hydroxy-4-(2-(4-isobutoxyphenyl)-2-methylpropanoyl)-2,3,4,5-tetrahydrobenzo[f][1,4]oxazepine-8-carboxamide;-   4-(1,1-dioxidotetrahydro-2H-thiopyran-4-carbonyl)-N-hydroxy-2,3,4,5-tetrahydrobenzo[f][1,4]oxazepine-8-carboxamide;-   N-hydroxy-4-(4-methoxycyclohexane-1-carbonyl)-2,3,4,5-tetrahydrobenzo[f][1,4]oxazepine-8-carboxamide;-   N-hydroxy-4-(1-(pyridin-2-yl)cyclopropane-1-carbonyl)-2,3,4,5-tetrahydrobenzo[f][1,4]oxazepine-8-carboxamide;-   N-hydroxy-4-(4-phenyltetrahydro-2H-pyran-4-carbonyl)-2,3,4,5-tetrahydrobenzo[f][1,4]oxazepine-8-carboxamide;-   N-hydroxy-4-(2-(pyridin-3-yl)propanoyl)-2,3,4,5-tetrahydrobenzo[f][1,4]oxazepine-8-carboxamide;-   N-hydroxy-4-(4-methoxy-2-(pyridin-2-yl)butanoyl)-2,3,4,5-tetrahydrobenzo[f][1,4]oxazepine-8-carboxamide;-   4-(3,3-difluorocyclopentane-1-carbonyl)-N-hydroxy-2,3,4,5-tetrahydrobenzo[f][1,4]oxazepine-8-carboxamide;-   N-hydroxy-4-(1-methylcyclopropane-1-carbonyl)-2,3,4,5-tetrahydrobenzo[f][1,4]oxazepine-8-carboxamide;-   N-hydroxy-4-(1-(methoxymethyl)cyclobutane-1-carbonyl)-2,3,4,5-tetrahydrobenzo[f][1,4]oxazepine-8-carboxamide;-   4-(1-((1H-imidazol-1-yl)methyl)cyclopropane-1-carbonyl)-N-hydroxy-2,3,4,5-tetrahydrobenzo[f][1,4]oxazepine-8-carboxamide;-   N-hydroxy-4-(1-(methoxymethyl)cyclopropane-1-carbonyl)-2,3,4,5-tetrahydrobenzo[f][1,4]oxazepine-8-carboxamide;-   N-hydroxy-4-(2-methyl-3-phenylpropanoyl)-2,3,4,5-tetrahydrobenzo[f][1,4]oxazepine-8-carboxamide;-   4-(1-acetylpyrrolidine-3-carbonyl)-N-hydroxy-2,3,4,5-tetrahydrobenzo[f][1,4]oxazepine-8-carboxamide;-   N-hydroxy-4-(1-methylcyclopentane-1-carbonyl)-2,3,4,5-tetrahydrobenzo[f][1,4]oxazepine-8-carboxamide;-   N-hydroxy-4-(1-(2-(trifluoromethyl)phenyl)cyclopropane-1-carbonyl)-2,3,4,5-tetrahydrobenzo[f][1,4]oxazepine-8-carboxamide;-   N-hydroxy-4-(1-(3-(trifluoromethyl)phenyl)cyclopropane-1-carbonyl)-2,3,4,5-tetrahydrobenzo[f][1,4]oxazepine-8-carboxamide;-   N-hydroxy-4-(tetrahydrofuran-3-carbonyl)-2,3,4,5-tetrahydrobenzo[f][1,4]oxazepine-8-carboxamide;-   N-hydroxy-4-(1-(4-(trifluoromethyl)phenyl)cyclopropane-1-carbonyl)-2,3,4,5-tetrahydrobenzo[f][1,4]oxazepine-8-carboxamide;-   N-hydroxy-4-(1-phenylcyclobutane-1-carbonyl)-2,3,4,5-tetrahydrobenzo[f][1,4]oxazepine-8-carboxamide;-   4-(1-benzylcyclopropane-1-carbonyl)-N-hydroxy-2,3,4,5-tetrahydrobenzo[f][1,4]oxazepine-8-carboxamide;-   N-hydroxy-4-(1-methoxycyclobutane-1-carbonyl)-2,3,4,5-tetrahydrobenzo[f][1,4]oxazepine-8-carboxamide;-   N-hydroxy-4-(1-(phenylsulfonyl)cyclopropane-1-carbonyl)-2,3,4,5-tetrahydrobenzo[f][1,4]oxazepine-8-carboxamide;-   4-(1-(4-fluorophenyl)cyclopropane-1-carbonyl)-N-hydroxy-2,3,4,5-tetrahydrobenzo[f][1,4]oxazepine-8-carboxamide;-   4-(1-(4-chlorophenyl)cyclopropane-1-carbonyl)-N-hydroxy-2,3,4,5-tetrahydrobenzo[f][1,4]oxazepine-8-carboxamide;-   N-hydroxy-4-(1-(4-methoxyphenyl)cyclopropane-1-carbonyl)-2,3,4,5-tetrahydrobenzo[f][1,4]oxazepine-8-carboxamide;-   4-(1-(3-chlorophenyl)cyclopropane-1-carbonyl)-N-hydroxy-2,3,4,5-tetrahydrobenzo[f][1,4]oxazepine-8-carboxamide;-   4-(1-(2-chlorophenyl)cyclopropane-1-carbonyl)-N-hydroxy-2,3,4,5-tetrahydrobenzo[f][1,4]oxazepine-8-carboxamide;-   N-hydroxy-4-(1-(3-methoxyphenyl)cyclopropane-1-carbonyl)-2,3,4,5-tetrahydrobenzo[f][1,4]oxazepine-8-carboxamide;-   N-hydroxy-4-(1-(pyridin-4-yl)cyclopropane-1-carbonyl)-2,3,4,5-tetrahydrobenzo[f][1,4]oxazepine-8-carboxamide;-   N-hydroxy-4-(1-(pyrazin-2-yl)cyclopropane-1-carbonyl)-2,3,4,5-tetrahydrobenzo[f][1,4]oxazepine-8-carboxamide;-   N-hydroxy-4-(1-phenoxycyclopropane-1-carbonyl)-2,3,4,5-tetrahydrobenzo[f][1,4]oxazepine-8-carboxamide;-   4-(1-((1H-pyrazol-1-yl)methyl)cyclopropane-1-carbonyl)-N-hydroxy-2,3,4,5-tetrahydrobenzo[f][1,4]oxazepine-8-carboxamide;-   N-hydroxy-4-(1-(thiophen-2-yl)cyclopropane-1-carbonyl)-2,3,4,5-tetrahydrobenzo[f][1,4]oxazepine-8-carboxamide;-   N-hydroxy-4-(oxetane-3-carbonyl)-2,3,4,5-tetrahydrobenzo[f][1,4]oxazepine-8-carboxamide;-   N-hydroxy-4-(3-methyloxetane-3-carbonyl)-2,3,4,5-tetrahydrobenzo[f][1,4]oxazepine-8-carboxamide;-   N-hydroxy-8-(tetrahydro-2H-pyran-4-carbonyl)-6,7,8,9-tetrahydropyrazino[2,3-f][1,4]oxazepine-3-carboxamide;-   8-(cyclohexanecarbonyl)-N-hydroxy-6,7,8,9-tetrahydropyrazino[2,3-f][1,4]oxazepine-3-carboxamide;-   (R)—N-hydroxy-2-isopropyl-4-(tetrahydro-2H-pyran-4-carbonyl)-2,3,4,5-tetrahydrobenzo[f][1,4]oxazepine-8-carboxamide;-   (R)—N-hydroxy-2-isopropyl-4-(1-methylcyclobutane-1-carbonyl)-2,3,4,5-tetrahydrobenzo[f][1,4]oxazepine-8-carboxamide;-   (R)-4-formyl-N-hydroxy-2-isopropyl-2,3,4,5-tetrahydrobenzo[f][1,4]oxazepine-8-carboxamide;-   (R)—N-hydroxy-2-(methoxymethyl)-4-(tetrahydro-2H-pyran-4-carbonyl)-2,3,4,5-tetrahydrobenzo[f][1,4]oxazepine-8-carboxamide;-   (R)—N-hydroxy-2-(methoxymethyl)-4-(1-methylcyclobutane-1-carbonyl)-2,3,4,5-tetrahydrobenzo[f][1,4]oxazepine-8-carboxamide;-   (R)-4-formyl-N-hydroxy-2-(methoxymethyl)-2,3,4,5-tetrahydrobenzo[f][1,4]oxazepine-8-carboxamide;-   (S)—N-hydroxy-2-(methoxymethyl)-4-(tetrahydro-2H-pyran-4-carbonyl)-2,3,4,5-tetrahydrobenzo[f][1,4]oxazepine-8-carboxamide;-   (S)—N-hydroxy-2-(methoxymethyl)-4-(1-methylcyclobutane-1-carbonyl)-2,3,4,5-tetrahydrobenzo[f][1,4]oxazepine-8-carboxamide;-   (S)-4-formyl-N-hydroxy-2-(methoxymethyl)-2,3,4,5-tetrahydrobenzo[f][1,4]oxazepine-8-carboxamide;-   (R)—N-hydroxy-2-phenyl-4-(tetrahydro-2H-pyran-4-carbonyl)-2,3,4,5-tetrahydrobenzo[f][1,4]oxazepine-8-carboxamide;-   (R)—N-hydroxy-4-(1-methylcyclobutane-1-carbonyl)-2-phenyl-2,3,4,5-tetrahydrobenzo[f][1,4]oxazepine-8-carboxamide;-   (R)-4-formyl-N-hydroxy-2-phenyl-2,3,4,5-tetrahydrobenzo[f][1,4]oxazepine-8-carboxamide;-   (S)—N-hydroxy-2-phenyl-4-(tetrahydro-2H-pyran-4-carbonyl)-2,3,4,5-tetrahydrobenzo[f][1,4]oxazepine-8-carboxamide;-   (S)—N-hydroxy-4-(1-methylcyclobutane-1-carbonyl)-2-phenyl-2,3,4,5-tetrahydrobenzo[f][1,4]oxazepine-8-carboxamide;-   (S)-4-formyl-N-hydroxy-2-phenyl-2,3,4,5-tetrahydrobenzo[f][1,4]oxazepine-8-carboxamide;-   (R)—N-hydroxy-4-(tetrahydro-2H-pyran-4-carbonyl)-3-(trifluoromethyl)-2,3,4,5-tetrahydrobenzo[f][1,4]oxazepine-8-carboxamide;-   (R)—N-hydroxy-4-(oxetane-3-carbonyl)-3-(trifluoromethyl)-2,3,4,5-tetrahydrobenzo[f][1,4]oxazepine-8-carboxamide;-   N-hydroxy-4-(tetrahydro-2H-pyran-4-carbonyl)-4,5-dihydro-2H-spiro[benzo[f][1,4]oxazepine-3,1′-cyclopropane]-8-carboxamide;-   (S)-3-ethyl-N-hydroxy-4-(tetrahydro-2H-pyran-4-carbonyl)-2,3,4,5-tetrahydrobenzo[f][1,4]oxazepine-8-carboxamide;-   (S)—N-hydroxy-3-isopropyl-4-(2-(tetrahydro-2H-pyran-4-yl)acetyl)-2,3,4,5-tetrahydrobenzo[f][1,4]oxazepine-8-carboxamide;-   (S)—N-hydroxy-3-isopropyl-4-(tetrahydro-2H-pyran-4-carbonyl)-2,3,4,5-tetrahydrobenzo[f][1,4]oxazepine-8-carboxamide;-   (S)—N-hydroxy-4-((1s,4R)-4-methoxycyclohexane-1-carbonyl)-3-methyl-2,3,4,5-tetrahydrobenzo[f][1,4]oxazepine-8-carboxamide;-   (S)—N-hydroxy-4-((1r,4S)-4-methoxycyclohexane-1-carbonyl)-3-methyl-2,3,4,5-tetrahydrobenzo[f][1,4]oxazepine-8-carboxamide;-   (S)-4-(1-formylpiperidine-4-carbonyl)-N-hydroxy-3-methyl-2,3,4,5-tetrahydrobenzo[f][1,4]oxazepine-8-carboxamide;-   (S)—N-hydroxy-4-(3-(methoxymethyl)oxetane-3-carbonyl)-3-methyl-2,3,4,5-tetrahydrobenzo[f][1,4]oxazepine-8-carboxamide;-   (S)—N-hydroxy-3-methyl-4-((R)-tetrahydro-2H-pyran-3-carbonyl)-2,3,4,5-tetrahydrobenzo[f][1,4]oxazepine-8-carboxamide;-   (S)—N-hydroxy-3-methyl-4-((S)-tetrahydro-2H-pyran-3-carbonyl)-2,3,4,5-tetrahydrobenzo[f][1,4]oxazepine-8-carboxamide;-   (S)—N-hydroxy-3-methyl-4-((R)-tetrahydrofuran-3-carbonyl)-2,3,4,5-tetrahydrobenzo[f][1,4]oxazepine-8-carboxamide;-   (S)—N-hydroxy-3-methyl-4-((S)-tetrahydrofuran-3-carbonyl)-2,3,4,5-tetrahydrobenzo[f][1,4]oxazepine-8-carboxamide;-   (S)—N-hydroxy-3-methyl-4-(2-(tetrahydro-2H-pyran-4-yl)acetyl)-2,3,4,5-tetrahydrobenzo[f][1,4]oxazepine-8-carboxamide;-   (S)—N-hydroxy-4-(4-(methoxymethyl)tetrahydro-2H-pyran-4-carbonyl)-3-methyl-2,3,4,5-tetrahydrobenzo[f][1,4]oxazepine-8-carboxamide;-   (S)-4-(3-ethyloxetane-3-carbonyl)-N-hydroxy-3-methyl-2,3,4,5-tetrahydrobenzo[f][1,4]oxazepine-8-carboxamide;-   (S)-4-(3-(4-fluorophenoxy)propanoyl)-N-hydroxy-3-methyl-2,3,4,5-tetrahydrobenzo[f][1,4]oxazepine-8-carboxamide;-   (S)—N-hydroxy-3-methyl-4-((1s,4R)-4-(trifluoromethoxy)cyclohexane-1-carbonyl)-2,3,4,5-tetrahydrobenzo[f][1,4]oxazepine-8-carboxamide;-   (S)—N-hydroxy-3-methyl-4-((1r,4S)-4-(trifluoromethoxy)cyclohexane-1-carbonyl)-2,3,4,5-tetrahydrobenzo[f][1,4]oxazepine-8-carboxamide;-   (S)—N-hydroxy-4-((1s,3R)-3-methoxycyclobutane-1-carbonyl)-3-methyl-2,3,4,5-tetrahydrobenzo[f][1,4]oxazepine-8-carboxamide;-   (S)—N-hydroxy-4-((1r,3S)-3-methoxycyclobutane-1-carbonyl)-3-methyl-2,3,4,5-tetrahydrobenzo[f][1,4]oxazepine-8-carboxamide;-   (S)-4-(3-(benzyloxy)cyclobutane-1-carbonyl)-N-hydroxy-3-methyl-2,3,4,5-tetrahydrobenzo[f][1,4]oxazepine-8-carboxamide;-   (3S)—N-hydroxy-3-methyl-4-(2-(tetrahydrofuran-2-yl)acetyl)-2,3,4,5-tetrahydrobenzo[f][1,4]oxazepine-8-carboxamide;-   (S)-4-(cyclohexanecarbonyl)-N-hydroxy-3-methyl-2,3,4,5-tetrahydrobenzo[f][1,4]oxazepine-8-carboxamide;-   (S)—N-hydroxy-4-(3-methoxypropanoyl)-3-methyl-2,3,4,5-tetrahydrobenzo[f][1,4]oxazepine-8-carboxamide;-   (S)-4-(4-fluorobenzoyl)-N-hydroxy-3-methyl-2,3,4,5-tetrahydrobenzo[f][1,4]oxazepine-8-carboxamide;-   (S)—N-hydroxy-3-methyl-4-propionyl-2,3,4,5-tetrahydrobenzo[f][1,4]oxazepine-8-carboxamide;-   (S)-4-(cyclopropanecarbonyl)-N-hydroxy-3-methyl-2,3,4,5-tetrahydrobenzo[f][1,4]oxazepine-8-carboxamide;-   (S)-4-(cyclobutanecarbonyl)-N-hydroxy-3-methyl-2,3,4,5-tetrahydrobenzo[f][1,4]oxazepine-8-carboxamide;-   (S)-4-(cyclopentanecarbonyl)-N-hydroxy-3-methyl-2,3,4,5-tetrahydrobenzo[f][1,4]oxazepine-8-carboxamide;-   (S)—N-hydroxy-4-isobutyryl-3-methyl-2,3,4,5-tetrahydrobenzo[f][1,4]oxazepine-8-carboxamide;-   (S)—N-hydroxy-4-(3-hydroxy-3-methylbutanoyl)-3-methyl-2,3,4,5-tetrahydrobenzo[f][1,4]oxazepine-8-carboxamide;-   (S)—N-hydroxy-4-(3-hydroxy-2,2-dimethylpropanoyl)-3-methyl-2,3,4,5-tetrahydrobenzo[f][1,4]oxazepine-8-carboxamide;-   (S)—N-hydroxy-4-(3-methoxy-3-methylbutanoyl)-3-methyl-2,3,4,5-tetrahydrobenzo[f][1,4]oxazepine-8-carboxamide;-   (S)-4-(4-fluorotetrahydro-2H-pyran-4-carbonyl)-N-hydroxy-3-methyl-2,3,4,5-tetrahydrobenzo[f][1,4]oxazepine-8-carboxamide;-   (3S)—N-hydroxy-3-methyl-4-(oxepane-4-carbonyl)-2,3,4,5-tetrahydrobenzo[f][1,4]oxazepine-8-carboxamide;-   (S)—N-hydroxy-3-methyl-4-((S)-2-methyltetrahydro-2H-pyran-2-carbonyl)-2,3,4,5-tetrahydrobenzo[f][1,4]oxazepine-8-carboxamide;-   (S)—N-hydroxy-3-methyl-4-((R)-2-methyltetrahydro-2H-pyran-2-carbonyl)-2,3,4,5-tetrahydrobenzo[f][1,4]oxazepine-8-carboxamide;-   (3S)—N-hydroxy-4-(2-isopropyltetrahydrofuran-3-carbonyl)-3-methyl-2,3,4,5-tetrahydrobenzo[f][1,4]oxazepine-8-carboxamide;-   (3S)-4-(5,5-dimethyltetrahydrofuran-2-carbonyl)-N-hydroxy-3-methyl-2,3,4,5-tetrahydrobenzo[f][1,4]oxazepine-8-carboxamide;-   (3S)—N-hydroxy-3-methyl-4-(2-methyltetrahydrofuran-2-carbonyl)-2,3,4,5-tetrahydrobenzo[f][1,4]oxazepine-8-carboxamide;-   (3S)-4-((2R)-7-oxabicyclo[2.2.1]heptane-2-carbonyl)-N-hydroxy-3-methyl-2,3,4,5-tetrahydrobenzo[f][1,4]oxazepine-8-carboxamide;-   (3S)-4-((2S)-7-oxabicyclo[2.2.1]heptane-2-carbonyl)-N-hydroxy-3-methyl-2,3,4,5-tetrahydrobenzo[f][1,4]oxazepine-8-carboxamide;-   (S)—N-hydroxy-4-(1-(methoxymethyl)cyclobutane-1-carbonyl)-3-methyl-2,3,4,5-tetrahydrobenzo[f][1,4]oxazepine-8-carboxamide;-   (S)—N-hydroxy-3-methyl-4-(3-((tetrahydro-2H-pyran-4-yl)oxy)propanoyl)-2,3,4,5-tetrahydrobenzo[f][1,4]oxazepine-8-carboxamide;-   (S)—N-hydroxy-4-(1-(methoxymethyl)cyclopropane-1-carbonyl)-3-methyl-2,3,4,5-tetrahydrobenzo[f][1,4]oxazepine-8-carboxamide;-   (S)—N-hydroxy-3-methyl-4-((1r,3S)-3-phenoxycyclobutane-1-carbonyl)-2,3,4,5-tetrahydrobenzo[f][1,4]oxazepine-8-carboxamide;-   (S)—N-hydroxy-3-methyl-4-((1s,3R)-3-phenoxycyclobutane-1-carbonyl)-2,3,4,5-tetrahydrobenzo[f][1,4]oxazepine-8-carboxamide;-   (S)—N-hydroxy-3-methyl-4-((2R,3S)-2-methyltetrahydro-2H-pyran-3-carbonyl)-2,3,4,5-tetrahydrobenzo[f][1,4]oxazepine-8-carboxamide;-   (S)—N-hydroxy-3-methyl-4-(3-(2,2,2-trifluoroethoxy)propanoyl)-2,3,4,5-tetrahydrobenzo[f][1,4]oxazepine-8-carboxamide;-   (S)—N-hydroxy-4-((2S,4S)-2-isopropyltetrahydro-2H-pyran-4-carbonyl)-3-methyl-2,3,4,5-tetrahydrobenzo[f][1,4]oxazepine-8-carboxamide;-   (S)-4-benzoyl-N-hydroxy-3-methyl-2,3,4,5-tetrahydrobenzo[f][1,4]oxazepine-8-carboxamide;-   (S)-4-(2-(4-fluorophenyl)-2-methylpropanoyl)-N-hydroxy-3-methyl-2,3,4,5-tetrahydrobenzo[f][1,4]oxazepine-8-carboxamide;-   (S)-4-(3-(4-fluorophenyl)-2,2-dimethylpropanoyl)-N-hydroxy-3-methyl-2,3,4,5-tetrahydrobenzo[f][1,4]oxazepine-8-carboxamide;-   (S)-4-((S)-2,2-dimethyltetrahydro-2H-pyran-4-carbonyl)-N-hydroxy-3-methyl-2,3,4,5-tetrahydrobenzo[f][1,4]oxazepine-8-carboxamide;-   (S)-4-((R)-2,2-dimethyltetrahydro-2H-pyran-4-carbonyl)-N-hydroxy-3-methyl-2,3,4,5-tetrahydrobenzo[f][1,4]oxazepine-8-carboxamide;-   (R)—N-hydroxy-3-(methoxymethyl)-4-(tetrahydro-2H-pyran-4-carbonyl)-2,3,4,5-tetrahydrobenzo[f][1,4]oxazepine-8-carboxamide;-   (S)—N-hydroxy-3-(methoxymethyl)-4-(tetrahydro-2H-pyran-4-carbonyl)-2,3,4,5-tetrahydrobenzo[f][1,4]oxazepine-8-carboxamide;-   N-hydroxy-4-(1-methoxycyclopropane-1-carbonyl)-2,3,4,5-tetrahydrobenzo[f][1,4]oxazepine-8-carboxamide;-   N-hydroxy-4-(4-methyltetrahydro-2H-pyran-4-carbonyl)-2,3,4,5-tetrahydrobenzo[f][1,4]oxazepine-8-carboxamide;-   4-(3-ethyloxetane-3-carbonyl)-N-hydroxy-2,3,4,5-tetrahydrobenzo[f][1,4]oxazepine-8-carboxamide;-   N-hydroxy-4-(1-methyl-1H-pyrrole-2-carbonyl)-2,3,4,5-tetrahydrobenzo[f][1,4]oxazepine-8-carboxamide;-   N-hydroxy-4-(1-methyl-1H-indole-2-carbonyl)-2,3,4,5-tetrahydrobenzo[f][1,4]oxazepine-8-carboxamide;-   4-(2-(3,5-bis(trifluoromethyl)phenyl)acetyl)-N-hydroxy-2,3,4,5-tetrahydrobenzo[f][1,4]oxazepine-8-carboxamide;-   4-(3,5-bis(trifluoromethyl)benzoyl)-N-hydroxy-2,3,4,5-tetrahydrobenzo[f][1,4]oxazepine-8-carboxamide;-   N-hydroxy-4-(1-methyl-1H-pyrazole-3-carbonyl)-2,3,4,5-tetrahydrobenzo[f][1,4]oxazepine-8-carboxamide;-   N-hydroxy-4-(2-mesitylacetyl)-2,3,4,5-tetrahydrobenzo[f][1,4]oxazepine-8-carboxamide;-   N8-hydroxy-N2,N2-dimethyl-4-(tetrahydro-2H-pyran-4-carbonyl)-2,3,4,5-tetrahydrobenzo[f][1,4]oxazepine-2,8-dicarboxamide;-   (R)—N-hydroxy-5-isopropyl-4-(tetrahydro-2H-pyran-4-carbonyl)-2,3,4,5-tetrahydrobenzo[f][1,4]oxazepine-8-carboxamide;-   (R)—N-hydroxy-5-isopropyl-4-(oxetane-3-carbonyl)-2,3,4,5-tetrahydrobenzo[f][1,4]oxazepine-8-carboxamide;-   (S)—N-hydroxy-5-isopropyl-4-(tetrahydro-2H-pyran-4-carbonyl)-2,3,4,5-tetrahydrobenzo[f][1,4]oxazepine-8-carboxamide;-   (S)—N-hydroxy-5-isopropyl-4-(oxetane-3-carbonyl)-2,3,4,5-tetrahydrobenzo[f][1,4]oxazepine-8-carboxamide;-   (R)—N-hydroxy-5-methyl-4-(1-methylcyclobutane-1-carbonyl)-2,3,4,5-tetrahydrobenzo[f][1,4]oxazepine-8-carboxamide;-   (R)—N-hydroxy-5-methyl-4-(tetrahydro-2H-pyran-4-carbonyl)-2,3,4,5-tetrahydrobenzo[f][1,4]oxazepine-8-carboxamide;-   (S)—N-hydroxy-5-methyl-4-(1-methylcyclobutane-1-carbonyl)-2,3,4,5-tetrahydrobenzo[f][1,4]oxazepine-8-carboxamide;-   (S)—N-hydroxy-5-methyl-4-(tetrahydro-2H-pyran-4-carbonyl)-2,3,4,5-tetrahydrobenzo[f][1,4]oxazepine-8-carboxamide;-   (S)—N-hydroxy-5-methyl-4-(4-methyltetrahydro-2H-pyran-4-carbonyl)-2,3,4,5-tetrahydrobenzo[f][1,4]oxazepine-8-carboxamide;-   (S)—N-hydroxy-5-methyl-4-(3-methyloxetane-3-carbonyl)-2,3,4,5-tetrahydrobenzo[f][1,4]oxazepine-8-carboxamide;-   (S)—N-hydroxy-5-methyl-4-(oxetane-3-carbonyl)-2,3,4,5-tetrahydrobenzo[f][1,4]oxazepine-8-carboxamide;-   (S)—N-hydroxy-4-(3-(methoxymethyl)oxetane-3-carbonyl)-5-methyl-2,3,4,5-tetrahydrobenzo[f][1,4]oxazepine-8-carboxamide;-   (S)—N-hydroxy-5-methyl-4-((S)-tetrahydro-2H-pyran-3-carbonyl)-2,3,4,5-tetrahydrobenzo[f][1,4]oxazepine-8-carboxamide;-   (S)—N-hydroxy-5-methyl-4-((R)-tetrahydro-2H-pyran-3-carbonyl)-2,3,4,5-tetrahydrobenzo[f][1,4]oxazepine-8-carboxamide;-   (S)—N-hydroxy-5-methyl-4-((S)-tetrahydrofuran-3-carbonyl)-2,3,4,5-tetrahydrobenzo[f][1,4]oxazepine-8-carboxamide;-   (S)—N-hydroxy-5-methyl-4-((R)-tetrahydrofuran-3-carbonyl)-2,3,4,5-tetrahydrobenzo[f][1,4]oxazepine-8-carboxamide;-   (S)—N-hydroxy-4-((1s,4R)-4-methoxycyclohexane-1-carbonyl)-5-methyl-2,3,4,5-tetrahydrobenzo[f][1,4]oxazepine-8-carboxamide;-   (S)—N-hydroxy-4-((1r,4S)-4-methoxycyclohexane-1-carbonyl)-5-methyl-2,3,4,5-tetrahydrobenzo[f][1,4]oxazepine-8-carboxamide;-   (S)—N-hydroxy-5-methyl-4-((R)-3-methyltetrahydrofuran-3-carbonyl)-2,3,4,5-tetrahydrobenzo[f][1,4]oxazepine-8-carboxamide;-   (S)—N-hydroxy-5-methyl-4-((S)-3-methyltetrahydrofuran-3-carbonyl)-2,3,4,5-tetrahydrobenzo[f][1,4]oxazepine-8-carboxamide;-   (S)—N-hydroxy-5-methyl-4-((R)-3-methyltetrahydro-2H-pyran-3-carbonyl)-2,3,4,5-tetrahydrobenzo[f][1,4]oxazepine-8-carboxamide;-   (S)—N-hydroxy-5-methyl-4-((S)-3-methyltetrahydro-2H-pyran-3-carbonyl)-2,3,4,5-tetrahydrobenzo[f][1,4]oxazepine-8-carboxamide;-   (S)—N-hydroxy-4-(4-(methoxymethyl)tetrahydro-2H-pyran-4-carbonyl)-5-methyl-2,3,4,5-tetrahydrobenzo[f][1,4]oxazepine-8-carboxamide;-   (2R,5R)—N-hydroxy-4-(tetrahydro-2H-pyran-4-carbonyl)-2,3,4,5-tetrahydro-2,5-methanobenzo[f][1,4]oxazepine-8-carboxamide;-   (2S,5S)—N-hydroxy-4-(tetrahydro-2H-pyran-4-carbonyl)-2,3,4,5-tetrahydro-2,5-methanobenzo[f][1,4]oxazepine-8-carboxamide;-   (S)—N-hydroxy-3-methyl-4-(2-methyl-2-(tetrahydro-2H-pyran-4-yl)propanoyl)-2,3,4,5-tetrahydrobenzo[f][1,4]oxazepine-8-carboxamide;-   (S)—N-hydroxy-3-methyl-4-(2-methyl-2-(pyridin-3-yl)propanoyl)-2,3,4,5-tetrahydrobenzo[f][1,4]oxazepine-8-carboxamide;-   (S)-4-(1H-benzo[d]imidazole-2-carbonyl)-N-hydroxy-3-methyl-2,3,4,5-tetrahydrobenzo[f][1,4]oxazepine-8-carboxamide;-   (S)—N-hydroxy-3-methyl-4-((S)-tetrahydro-2H-pyran-2-carbonyl)-2,3,4,5-tetrahydrobenzo[f][1,4]oxazepine-8-carboxamide;-   (S)—N-hydroxy-3-methyl-4-((R)-tetrahydro-2H-pyran-2-carbonyl)-2,3,4,5-tetrahydrobenzo[f][1,4]oxazepine-8-carboxamide;-   (S)—N-hydroxy-3-methyl-4-((R)-3-methyltetrahydrofuran-3-carbonyl)-2,3,4,5-tetrahydrobenzo[f][1,4]oxazepine-8-carboxamide;-   (S)—N-hydroxy-3-methyl-4-((S)-3-methyltetrahydrofuran-3-carbonyl)-2,3,4,5-tetrahydrobenzo[f][1,4]oxazepine-8-carboxamide;-   N-hydroxy-4-(1-methylcyclobutane-1-carbonyl)-2-oxo-2,3,4,5-tetrahydro-1H-benzo[e][1,4]diazepine-7-carboxamide;-   (S)-3-benzyl-N-hydroxy-4-(tetrahydro-2H-pyran-4-carbonyl)-2,3,4,5-tetrahydrobenzo[f][1,4]oxazepine-8-carboxamide;    or-   N-hydroxy-4-(tetrahydro-2H-pyran-4-carbonyl)-3-(tetrahydro-2H-pyran-4-yl)-2,3,4,5-tetrahydrobenzo[f][1,4]oxazepine-8-carboxamide.

In an illustrative embodiment, the compound of Formula I is:

-   (R)—N-hydroxy-4-(tetrahydro-2H-pyran-4-carbonyl)-3-((trifluoromethoxy)methyl)-2,3,4,5-tetrahydrobenzo[f][1,4]oxazepine-8-carboxamide;-   (R)—N-hydroxy-4-(4-methyltetrahydro-2H-pyran-4-carbonyl)-3-((trifluoromethoxy)methyl)-2,3,4,5-tetrahydrobenzo[f][1,4]oxazepine-8-carboxamide;-   (3S)—N-hydroxy-3,5-dimethyl-4-(tetrahydro-2H-pyran-4-carbonyl)-2,3,4,5-tetrahydrobenzo[f][1,4]oxazepine-8-carboxamide;-   (3S)—N-hydroxy-3,5-dimethyl-4-(4-methyltetrahydro-2H-pyran-4-carbonyl)-2,3,4,5-tetrahydrobenzo[f][1,4]oxazepine-8-carboxamide;-   (S)-6-fluoro-N-hydroxy-3-methyl-4-(tetrahydro-2H-pyran-4-carbonyl)-2,3,4,5-tetrahydrobenzo[f][1,4]oxazepine-8-carboxamide;    or-   (S)-6-fluoro-N-hydroxy-3-methyl-4-(4-methyltetrahydro-2H-pyran-4-carbonyl)-2,3,4,5-tetrahydrobenzo[f][1,4]oxazepine-8-carboxamide.

In another embodiment of the disclosure, the compounds of Formula I areenantiomers. In some embodiments the compounds are the (S)-enantiomer.In other embodiments the compounds are the (R)-enantiomer. In someembodiment, the (R)- or (S)-enantiomeric configuration may be assignedto each molecule. In other embodiments, the (R)- or (S)-enantiomericconfiguration may not be assigned to the molecules despite theenantiomeric purification or separation of the molecules. In yet otherembodiments, the compounds of Formula I may be (+) or (−) enantiomers.

It should be understood that all isomeric forms are included within thepresent disclosure, including mixtures thereof. If the compound containsa double bond, the substituent may be in the E or Z configuration or cisor trans configuration. If the compound contains a disubstitutedcycloalkyl, the cycloalkyl substituent may have a cis- or transconfiguration. All tautomeric forms are also intended to be included. Insome embodiment, the cis or trans configuration may be assigned to eachmolecule. In other embodiments, the cis or trans configuration may notbe assigned to the molecules despite the chemical purification orseparation of the diastereomers.

Methods of Synthesizing the Disclosed Compounds

The compounds of the present disclosure may be made by a variety ofmethods, including standard chemistry. Suitable synthetic routes aredepicted in the schemes given below.

The compounds of Formula I may be prepared by methods known in the artof organic synthesis as set forth in part by the following syntheticschemes and examples. In the schemes described below, it is wellunderstood that protecting groups for sensitive or reactive groups areemployed where necessary in accordance with general principles orchemistry. Protecting groups are manipulated according to standardmethods of organic synthesis (T. W. Greene and P. G. M. Wuts,“Protective Groups in Organic Synthesis”, Third edition, Wiley, New York1999). These groups are removed at a convenient stage of the compoundsynthesis using methods that are readily apparent to those skilled inthe art. The selection processes, as well as the reaction conditions andorder of their execution, shall be consistent with the preparation ofcompounds of Formula I.

Those skilled in the art will recognize if a stereocenter exists in thecompounds of Formula I. Accordingly, the present disclosure includesboth possible stereoisomers (unless specified in the synthesis) andincludes not only racemic compounds but the individual enantiomersand/or diastereomers as well. When a compound is desired as a singleenantiomer or diastereomer, it may be obtained by stereospecificsynthesis or by resolution of the final product or any convenientintermediate. Resolution of the final product, an intermediate, or astarting material may be affected by any suitable method known in theart. See, for example, “Stereochemistry of Organic Compounds” by E. L.Eliel, S. H. Wilen, and L. N. Mander (Wiley-Interscience, 1994).

The compounds described herein may be made from commercially availablestarting materials or synthesized using known organic, inorganic, and/orenzymatic processes.

Preparation of Compounds

The compounds of the present disclosure can be prepared in a number ofways well known to those skilled in the art of organic synthesis. By wayof example, compounds of the present disclosure can be synthesized usingthe methods described below, together with synthetic methods known inthe art of synthetic organic chemistry, or variations thereon asappreciated by those skilled in the art. These methods include, but arenot limited, to those methods described below. Compounds of the presentdisclosure can be synthesized by following the steps outlined in GeneralSchemes 1, 2, 3, 4, and 5 which comprise different sequences ofassembling intermediates 2a, 2b, 2c, 2d, 2e, 2f, 2g, 2h, 2i, 2j, 2k, 2m,2n, 2o, 2p, 2q, 2r, 2s, 2t, 2u, 2v, 2w, 2x, 2y, 2z, 2aa, 2bb, and 2cc.Starting materials are either commercially available or made by knownprocedures in the reported literature or as illustrated.

wherein L, R, R¹, R², R^(1′), R^(2′), Y¹ and Y² are defined as inFormula (I).

The general way of preparing target molecules of Formula (I) by usingintermediates 2a, 2b, 2c, 2d, and 2e is outlined in General Scheme 1.Nucleophilic addition of alcohol 2b to Intermediate 2a using a base,e.g., potassium carbonate (K₂CO₃), in a solvent, e.g., acetonitrile(MeCN), provides Intermediate 2c. Cyclization of Intermediate 2c in thepresence of a catalytic amount of a metal catalyst, e.g., copper iodide(CuI), palladium acetate (Pd(OAc)₂), etc., and a base, e.g., potassiumcarbonate (K₂CO₃), in a solvent, e.g., isopropanol (i-PrOH), optionallyat elevated temperature provides Intermediate 2d. Acylation ofIntermediate 2d with an acyl halide in the presence of a base, e.g.,sodium hydride (NaH), and optionally at elevated temperatures providesIntermediate 2e. Alternatively, coupling of a carboxylic acid withIntermediate 2d under standard coupling conditions using a couplingreagent, e.g.,1-[bis(dimethylamino)methylene]-1H-1,2,3-triazolo[4,5-b]pyridinium3-oxidehexafluoro-phosphate (HATU), orO-benzotriazole-N,N,N′,N′-tetramethyl-uronium-hexafluoro-phosphate(HBTU), and a base, e.g., triethylamine or N,N-diisopropylethylamine(DIPEA), in a solvent, e.g., dichloromethane or DMF providesIntermediate 2e. Intermediate 2e can also be obtained by reacting 2dwith a carboxylic acid and an activating agent, e.g.,4-(4,6-dimethoxy-1,3,5-triazin-2-yl)-4-methylmorpholinium chloride(DMTMM), in a solvent, e.g., dimethylformamide (DMF). Treatment ofIntermediate 2e with hydroxylamine and a base, e.g., aqueous sodiumhydroxide (aq. NaOH) in a solvent, e.g., tetrahydrofuran (TIF) and/ormethanol (MeOH), provides compounds of Formula (I).

wherein L, R, R^(1′), and R^(2′) are defined as in Formula (I).

The general way of preparing target molecules of Formula (I) by usingintermediates 2f, 2g, 2h, 2i, 2j, and 2k is outlined in General Scheme2. Nucleophilic addition of amine 2g to Intermediate 2f using a base,e.g., N,N-diisopropylethylamine (DIEA), and in a solvent, e.g., MeCN,dichloromethane (DCM), or DMF, provides Intermediate 2h. Protection ofthe amine group in intermediate 2h with a typical acid labile protectinggroup (e.g., t-butoxycarbonyl (Boc)) using an alkyl chloride and4-Dimethylaminopyridine (DMAP), in a solvent e.g., DCM ortetrahydrofuran (THF), followed by hydrogenation in the presence of ametal catalyst, e.g., palladium on carbon, and hydrogen (H₂) gas in asolvent, e.g., DCM, provides Intermediate 2i. Cyclization ofIntermediate 2i in the presence of a base, e.g., potassium carbonate(K₂CO₃), and in a solvent, e.g., isopropanol (i-PrOH), optionally atelevated temperatures provides Intermediate 2j. Acylation ofIntermediate 2j with an acyl halide in the presence of a base, e.g.,sodium hydride (NaH), and optionally at elevated temperatures providesIntermediate 2k. Alternatively, coupling of a carboxylic acid withIntermediate 2j under standard coupling conditions using a couplingreagent, e.g.,1-[bis(dimethylamino)methylene]-1H-1,2,3-triazolo[4,5-b]pyridinium3-oxidehexafluoro-phosphate (HATU), orO-benzotriazole-N,N,N′,N′-tetramethyl-uronium-hexafluoro-phosphate(HBTU), and a base, e.g., triethylamine or N,N-diisopropylethylamine(DIPEA), in a solvent, e.g., dichloromethane or DMF providesIntermediate 2k. Intermediate 2k can also be obtained by reacting 2jwith a carboxylic acid and an activating agent, e.g.,4-(4,6-dimethoxy-1,3,5-triazin-2-yl)-4-methylmorpholinium chloride(DMTMM), in a solvent, e.g., dimethylformamide (DMF). Treatment ofIntermediate 2k with hydroxylamine and a base, e.g., aqueous sodiumhydroxide (aq. NaOH) in a solvent, e.g., tetrahydrofuran (TIF) and/ormethanol (MeOH), provides compounds of Formula (I).

wherein L, R, R^(1′), and R^(2′) are defined as in Formula (I).

The general way of preparing target molecules of Formula (I) by usingintermediates 2m, 2n, 2o, 2p, and 2q, is outlined in General Scheme 3.Sulfonylation of alcohol 2n with Intermediate 2m in the presence of ametal oxide, e.g., MgO, and in a solvent, e.g., THE and or water (H₂O),provides Intermediate 2o. Cyclization of Intermediate 20 in the presenceof a base, e.g., sodium methoxide (NaOMe), and in a solvent, e.g.,methanol (MeOH), i-PrOH, etc., provides Intermediate 2p. Acylation ofIntermediate 2p with an acyl halide in the presence of a base, e.g.,sodium hydride (NaH), and optionally at elevated temperatures providesIntermediate 2q. Alternatively, coupling of a carboxylic acid withIntermediate 2p under standard coupling conditions using a couplingreagent, e.g.,1-[bis(dimethylamino)methylene]-1H-1,2,3-triazolo[4,5-b]pyridinium3-oxidehexafluoro-phosphate (HATU), orO-benzotriazole-N,N,N′,N′-tetramethyl-uronium-hexafluoro-phosphate(HBTU), and a base, e.g., triethylamine or N,N-diisopropylethylamine(DIPEA), in a solvent, e.g., dichloromethane or DMF providesIntermediate 2q. Intermediate 2q can also be obtained by reacting 2pwith a carboxylic acid and an activating agent, e.g.,4-(4,6-dimethoxy-1,3,5-triazin-2-yl)-4-methylmorpholinium chloride(DMTMM), in a solvent, e.g., dimethylformamide (DMF). Treatment ofIntermediate 2q with hydroxylamine and a base, e.g., aqueous sodiumhydroxide (aq. NaOH), in a solvent, e.g., tetrahydrofuran (TIF) and/ormethanol (MeOH), provides compounds of Formula (I).

wherein L, R, R^(1′), and R^(2′) are defined as in Formula (I).

The general way of preparing target molecules of Formula (I) by usingintermediates 2r, 2s, 2t, 2u, and 2v, is outlined in General Scheme 4.Intermediate 2t can be obtained by alkylation of 2s with phenol 2r usinga Mitsunobu reagent (e.g., diethyl azodicarboxylate (DEAD) ordiisopropyl azodicarboxylate (DIAD)), and triphenyl phosphine in asolvent, e.g., tetrahydrofuran (THF), dichloromethane (DCM).Deprotection of intermediate 2t using a strong acid such astrifluoroacetic acid (TFA) in a solvent, e.g., dichloromethane (DCM),followed by cyclization in the presence of a base, e.g., triethylamine(Et₃N), and optionally in a solvent, e.g., THF, MeOH, etc., at elevatedtemperature provides Intermediate 2u. Acylation of Intermediate 2u withan acyl halide in the presence of a base, e.g., sodium hydride (NaH),and optionally at elevated temperatures provides Intermediate 2v.Alternatively, coupling of a carboxylic acid with Intermediate 2u understandard coupling conditions using a coupling reagent, e.g.,1-[bis(dimethylamino)methylene]-1H-1,2,3-triazolo[4,5-b]pyridinium3-oxidehexafluoro-phosphate (HATU), orO-benzotriazole-N,N,N′,N′-tetramethyl-uronium-hexafluoro-phosphate(HBTU), and a base, e.g., triethylamine or N,N-diisopropylethylamine(DIPEA), in a solvent, e.g., dichloromethane or DMF providesIntermediate 2v. Intermediate 2v can also be obtained by reacting 2uwith a carboxylic acid and an activating agent, e.g.,4-(4,6-dimethoxy-1,3,5-triazin-2-yl)-4-methylmorpholinium chloride(DMTMM), in a solvent, e.g., dimethylformamide (DMF). Treatment ofIntermediate 2v with hydroxylamine and a base, e.g., aqueous sodiumhydroxide (aq. NaOH) in a solvent, e.g., tetrahydrofuran (TIF) and/ormethanol (MeOH), provides compounds of Formula (I).

wherein L, R, R^(1′), and R^(2′) are defined as in Formula (I).

The general way of preparing target molecules of Formula (I) by usingintermediates 2w, 2x, 2y, 2z, 2aa, 2bb, and 2cc, is outlined in GeneralScheme 5. Alkylation of phenol 2w with Intermediate 2× using potassiumiodide (KI) and a base, e.g., potassium carbonate (K₂CO₃), in a solvent,e.g., MeCN, THF, etc., provides Intermediate 2y. Deprotection ofIntermediate 2y using a strong acid such as trifluoroacetic acid (TFA)in a solvent, e.g., dichloromethane (DCM) followed by cyclization viaintramolecular reductive amination in the presence of sodium borohydrideor sodium cyanoborohydride in a solvent, e.g., THF, MeOH, etc., providesIntermediate 2z. Protection of the amine group in intermediate 2z with atypical acid labile protecting group (e.g., t-butoxycarbonyl (Boc))using an alkyl chloride and optionally 4-DMAP in a solvent e.g., DCM ortetrahydrofuran (THF), followed by carbonylation in the presence of ametal catalyst, e.g.,[1,1′-Bis(diphenylphosphino)ferrocene]palladium(II) dichloride, andcarbon monoxide (CO) gas in a solvent, e.g., DCM, provides Intermediate2aa. Deprotection of intermediate 2aa using a strong acid such astrifluoroacetic acid (TFA) in a solvent, e.g., dichloromethane (DCM)provides Intermediate 2bb. Acylation of Intermediate 2bb with an acylhalide in the presence of a base, e.g., sodium hydride (NaH), andoptionally at elevated temperatures provides Intermediate 2cc.Alternatively, coupling of a carboxylic acid with Intermediate 2bb understandard coupling conditions using a coupling reagent, e.g.,1-[bis(dimethylamino)methylene]-1H-1,2,3-triazolo[4,5-b]pyridinium3-oxidehexafluoro-phosphate (HATU), orO-benzotriazole-N,N,N′,N′-tetramethyl-uronium-hexafluoro-phosphate(HBTU), and a base, e.g., triethylamine or N,N-diisopropylethylamine(DIPEA), in a solvent, e.g., dichloromethane or DMF providesIntermediate 2cc. Intermediate 2cc can also be obtained by reacting 2bbwith a carboxylic acid and an activating agent, e.g.,4-(4,6-dimethoxy-1,3,5-triazin-2-yl)-4-methylmorpholinium chloride(DMTMM), in a solvent, e.g., dimethylformamide (DMF). Treatment ofIntermediate 2cc with hydroxylamine and a base, e.g., aqueous sodiumhydroxide (aq. NaOH), in a solvent, e.g., tetrahydrofuran (TIF) and/ormethanol (MeOH), provides compounds of Formula (I).

Methods of Using the Disclosed Compounds

Another aspect of the disclosure relates to a method of treating adisease associated with HDAC, e.g., HDAC6, modulation in a subject inneed thereof. The method involves administering to a patient in need oftreatment for diseases or disorders associated with HDAC, e.g., HDAC6,modulation an effective amount of a compound of Formula I. In anembodiment, the disease can be, but is not limited to, cancer,neurodegenerative disease, neurodevelopmental disease, inflammatory orautoimmune disease, infection, metabolic disease, hematologic disease,or cardiovascular disease.

Another aspect of the disclosure is directed to a method of inhibitingan HDAC, e.g., HDAC6. The method involves administering to a patient inneed thereof an effective amount of Formula I.

The present disclosure relates to compositions capable of modulating theactivity of (e.g., inhibiting) HDACs, for instance HDAC6. The presentdisclosure also relates to the therapeutic use of such compounds.

One therapeutic use of the compounds of the present disclosure is totreat proliferative diseases or disorders such as cancer. Cancer can beunderstood as abnormal or unregulated cell growth within a patient andcan include but is not limited to lung cancer, ovarian cancer, breastcancer, prostate cancer, pancreatic cancer, hepatocellular cancer, renalcancer and leukemias such as acute myeloid leukemia and acutelymphoblastic leukemia. Additional cancer types include T-cell lymphoma(e.g., cutaneous T-cell lymphoma, peripheral T-cell lymphoma), andmultiple myeloma.

One therapeutic use of the compounds of the present disclosure is totreat neurological diseases or disorders or neurodegeneration.Neurological disorders are understood as disorders of the nervous system(e.g., the brain and spinal cord). Neurological disorders orneurodegenerative diseases can include but are not limited to epilepsy,attention deficit disorder (ADD), Alzheimer's disease, Parkinson'sDisease, Huntington's Disease, amyotrophic lateral sclerosis, spinalmuscular atrophy, essential tremor, central nervous system trauma causedby tissue injury, oxidative stress-induced neuronal or axomaldegeneration, and multiple sclerosis.

Another therapeutic use of the compounds of the present disclosure is totreat neurodevelopmental disorders. Neurodevelopmental disorders caninclude, but are not limited to, Rett syndrome.

Another therapeutic use of the compounds of the present disclosure isalso to treat inflammatory diseases or disorders. Inflammation can beunderstood as a host's response to an initial injury or infection.Symptoms of inflammation can include but are not limited to redness,swelling, pain, heat and loss of function. Inflammation may be caused bythe upregulation of pro-inflammatory cytokines such as IL-1β, andincreased expression of the FOXP3 transcription factor.

Another therapeutic use of the compounds of the present disclosure isalso to treat autoimmune diseases or disorders. Autoimmune disorders areunderstood as disorders wherein a host's own immune system responds totissues and substances occurring naturally in the host's body.Autoimmune diseases can include but are not limited to Rheumatoidarthritis, spondylitis arthritis, psoriatic arthritis, multiplesclerosis, systemic lupus erythematosus, inflammatory bowel disease,graft versus host disease, transplant rejection, fibrotic disease,Crohn's Disease, type-1 diabetes, Eczema, and psoriasis.

Another therapeutic use of the compounds of the present disclosure isalso to treat infectious diseases or disorders. Infections or infectiousdiseases are caused by the invasion of a foreign pathogen. The infectionmay be caused by, for instance, a bacteria, a fungus, or virus. Forexample, a bacterial infection may be caused by a E. coli.

Yet another therapeutic use of the compounds of the present disclosureis also to treat metabolic diseases or disorders. Metabolic diseases canbe characterized as abnormalities in the way that a subject storesenergy. Metabolic disorders can include but are not limited to metabolicsyndrome, diabetes, obesity, high blood pressure, and heart failure.

Yet another therapeutic use of the compounds of the present disclosureis also to treat hematologic disorders. Hematologic diseases primarilyaffect the blood. Hematologic disorders can include but are not limitedto anemia, lymphoma, and leukemia.

Yet another therapeutic use of the compounds of the present disclosureis also to treat cardiovascular diseases or disorders. Cardiovasculardiseases affect the heart and blood vessels of a patient. Exemplaryconditions include but are not limited to cardiovascular stress,pressure overload, chronic ischemia, infarction-reperfusion injury,hypertension, atherosclerosis, peripheral artery disease, and heartfailure.

Another aspect of the present disclosure relates to a compound ofFormula (I), or a pharmaceutically acceptable salt, hydrate, solvate,prodrug, stereoisomer, or tautomer thereof, for use in treating orpreventing a disease associated with HDAC6 modulation. In someembodiments, the disease is cancer, neurodegenerative disease,neurodevelopmental disorder, inflammatory or autoimmune disease,infection, metabolic disease, hematologic disease, or cardiovasculardisease. In some embodiments, the compound inhibits a histonedeacetylase. In another embodiment, the compound inhibits azinc-dependent histone deacetylase. In another embodiment, the compoundinhibits the HDAC6 isozyme zinc-dependent histone deacetylase.

In another aspect, the present disclosure relates to the use of acompound of Formula (I), or a pharmaceutically acceptable salt, hydrate,solvate, prodrug, stereoisomer, or tautomer thereof, in the manufactureof a medicament for treating or preventing a disease associated withHDAC6 modulation. In some embodiments, the disease is cancer,neurodegenerative disease, neurodevelopmental disorder, inflammatory orautoimmune disease, infection, metabolic disease, hematologic disease,or cardiovascular disease. In some embodiments, the compound inhibits ahistone deacetylase. In another embodiment, the compound inhibits azinc-dependent histone deacetylase. In another embodiment, the compoundinhibits the HDAC6 isozyme zinc-dependent histone deacetylase.

In some embodiments, the cancer is cutaneous T-cell lymphoma, peripheralT-cell lymphoma, multiple myeloma, leukemia, lung, ovarian, breast,prostate, pancreatic, hepatocellular or renal cancer. In otherembodiments, the neurodegenerative disease is Alzheimer's, Huntington's,Parkinson's, Amyotrophic Lateral Sclerosis, or spinal muscular atrophy.In other embodiments, the neurodevelopmental disorder is Rett syndrome.In yet other embodiments, the inflammatory or autoimmune disease isrheumatoid arthritis, spondylitis arthritis, psoriatic arthritis,psoriasis, multiple sclerosis, systemic lupus erythematosus,inflammatory bowel diseases, graft versus host disease, transplantrejection or fibrotic disease.

The disclosed compound can be administered in effective amounts to treator prevent a disorder and/or prevent the development thereof insubjects.

Administration of the disclosed compounds can be accomplished via anymode of administration for therapeutic agents. These modes includesystemic or local administration such as oral, nasal, parenteral,transdermal, subcutaneous, vaginal, buccal, rectal or topicaladministration modes.

Depending on the intended mode of administration, the disclosedcompositions can be in solid, semi-solid or liquid dosage form, such as,for example, injectables, tablets, suppositories, pills, time-releasecapsules, elixirs, tinctures, emulsions, syrups, powders, liquids,suspensions, or the like, sometimes in unit dosages and consistent withconventional pharmaceutical practices. Likewise, they can also beadministered in intravenous (both bolus and infusion), intraperitoneal,subcutaneous or intramuscular form, all using forms well known to thoseskilled in the pharmaceutical arts.

Illustrative pharmaceutical compositions are tablets and gelatincapsules comprising a Compound of the Disclosure and a pharmaceuticallyacceptable carrier, such as a) a diluent, e.g., purified water,triglyceride oils, such as hydrogenated or partially hydrogenatedvegetable oil, or mixtures thereof, corn oil, olive oil, sunflower oil,safflower oil, fish oils, such as EPA or DHA, or their esters ortriglycerides or mixtures thereof, omega-3 fatty acids or derivativesthereof, lactose, dextrose, sucrose, mannitol, sorbitol, cellulose,sodium, saccharin, glucose and/or glycine; b) a lubricant, e.g., silica,talcum, stearic acid, its magnesium or calcium salt, sodium oleate,sodium stearate, magnesium stearate, sodium benzoate, sodium acetate,sodium chloride and/or polyethylene glycol; for tablets also; c) abinder, e.g., magnesium aluminum silicate, starch paste, gelatin,tragacanth, methylcellulose, sodium carboxymethylcellulose, magnesiumcarbonate, natural sugars such as glucose or beta-lactose, cornsweeteners, natural and synthetic gums such as acacia, tragacanth orsodium alginate, waxes and/or polyvinylpyrrolidone, if desired; d) adisintegrant, e.g., starches, agar, methyl cellulose, bentonite, xanthangum, alginic acid or its sodium salt, or effervescent mixtures; e)absorbent, colorant, flavorant and sweetener; f) an emulsifier ordispersing agent, such as Tween 80, Labrasol, HPMC, DOSS, caproyl 909,labrafac, labrafil, peceol, transcutol, capmul MCM, capmul PG-12, captex355, gelucire, vitamin E TGPS or other acceptable emulsifier; and/or g)an agent that enhances absorption of the compound such as cyclodextrin,hydroxypropyl-cyclodextrin, PEG400, PEG200.

Liquid, particularly injectable, compositions can, for example, beprepared by dissolution, dispersion, etc. For example, the disclosedcompound is dissolved in or mixed with a pharmaceutically acceptablesolvent such as, for example, water, saline, aqueous dextrose, glycerol,ethanol, and the like, to thereby form an injectable isotonic solutionor suspension. Proteins such as albumin, chylomicron particles, or serumproteins can be used to solubilize the disclosed compounds.

The disclosed compounds can be also formulated as a suppository that canbe prepared from fatty emulsions or suspensions; using polyalkyleneglycols such as propylene glycol, as the carrier.

The disclosed compounds can also be administered in the form of liposomedelivery systems, such as small unilamellar vesicles, large unilamellarvesicles and multilamellar vesicles. Liposomes can be formed from avariety of phospholipids, containing cholesterol, stearylamine orphosphatidylcholines. In some embodiments, a film of lipid components ishydrated with an aqueous solution of drug to a form lipid layerencapsulating the drug, as described in U.S. Pat. No. 5,262,564.

Disclosed compounds can also be delivered by the use of monoclonalantibodies as individual carriers to which the disclosed compounds arecoupled. The disclosed compounds can also be coupled with solublepolymers as targetable drug carriers. Such polymers can includepolyvinylpyrrolidone, pyran copolymer,polyhydroxypropylmethacrylamide-phenol,polyhydroxyethylaspanamidephenol, or polyethyleneoxidepolylysinesubstituted with palmitoyl residues. Furthermore, the disclosedcompounds can be coupled to a class of biodegradable polymers useful inachieving controlled release of a drug, for example, polylactic acid,polyepsilon caprolactone, polyhydroxy butyric acid, polyorthoesters,polyacetals, polydihydropyrans, polycyanoacrylates and cross-linked oramphipathic block copolymers of hydrogels. In one embodiment, disclosedcompounds are not covalently bound to a polymer, e.g., a polycarboxylicacid polymer, or a polyacrylate.

Parental injectable administration is generally used for subcutaneous,intramuscular or intravenous injections and infusions. Injectables canbe prepared in conventional forms, either as liquid solutions orsuspensions or solid forms suitable for dissolving in liquid prior toinjection.

Another aspect of the disclosure relates to a pharmaceutical compositioncomprising a compound of Formula I and a pharmaceutically acceptablecarrier. The pharmaceutically acceptable carrier can further include anexcipient, diluent, or surfactant.

Compositions can be prepared according to conventional mixing,granulating or coating methods, respectively, and the presentpharmaceutical compositions can contain from about 0.1% to about 99%,from about 5% to about 90%, or from about 1% to about 20% of thedisclosed compound by weight or volume.

The dosage regimen utilizing the disclosed compound is selected inaccordance with a variety of factors including type, species, age,weight, sex and medical condition of the patient; the severity of thecondition to be treated; the route of administration; the renal orhepatic function of the patient; and the particular disclosed compoundemployed. A physician or veterinarian of ordinary skill in the art canreadily determine and prescribe the effective amount of the drugrequired to prevent, counter or arrest the progress of the condition.

Effective dosage amounts of the disclosed compounds, when used for theindicated effects, range from about 0.5 mg to about 5000 mg of thedisclosed compound as needed to treat the condition. Compositions for invivo or in vitro use can contain about 0.5, 5, 20, 50, 75, 100, 150,250, 500, 750, 1000, 1250, 2500, 3500, or 5000 mg of the disclosedcompound, or, in a range of from one amount to another amount in thelist of doses. In one embodiment, the compositions are in the form of atablet that can be scored.

Without wishing to be bound by any particular theory, the compounds ofthe present disclosure can inhibit HDACs such as HDAC6 by interactingwith the zinc (Zn²⁺) ion in the protein's active site via the hydroxamicacid group bound to the aromatic ring of the compound. The binding canprevent the zinc ion from interacting with its natural substrates, thusinhibiting the enzyme.

EXAMPLES

The disclosure is further illustrated by the following examples andsynthesis examples, which are not to be construed as limiting thisdisclosure in scope or spirit to the specific procedures hereindescribed. It is to be understood that the examples are provided toillustrate certain embodiments and that no limitation to the scope ofthe disclosure is intended thereby. It is to be further understood thatresort may be had to various other embodiments, modifications, andequivalents thereof which may suggest themselves to those skilled in theart without departing from the spirit of the present disclosure and/orscope of the appended claims.

The present disclosure includes a number of unique features andadvantages compared with other inhibitors of HDAC enzymes, for instanceHDAC6. For instance, the present disclosure features a unique class ofsmall molecule therapeutic agents of Formula I. The compounds weredesigned by using crystal structure information of HDAC ligand-proteincomplexes as well as advanced computational chemistry tools. Thesetechniques led to the development of new chemical scaffolds that wereiteratively refined to optimize key recognition features between theligand and receptor known to be necessary for potency.

Definitions used in the following examples and elsewhere herein are:

-   -   Boc: t-butoxycarbonyl    -   BOP: (benzotriazol-1-yloxy)tris(dimethylamino)phosphonium        hexafluorophosphate    -   CCl₄: carbon tetrachloride    -   CDCl₃: deuterated chloroform    -   CH₂Cl₂: methylene chloride, dichloromethane    -   CO (g): carbon monoxide gas    -   Cs₂CO₃: cesium carbonate    -   CuI copper (I) iodide    -   DIEA: diisopropylethylamine    -   DMA: dimethylacetamide    -   DMC: 2-chloro-1,3-dimethylimidazolinium chloride    -   DMF: N,N-dimethylformamide    -   DMSO: dimethylsulfoxide    -   DMTMM: 4-(4,6-Dimethoxy-1,3,5-triazin-2-yl)-4-methylmorpholinium        chloride    -   Et₃N: triethylamine    -   Et₂O: diethyl ether    -   EtOAc: ethyl acetate    -   h: hours    -   H₂O: water    -   HATU:        1-[bis(dimethylamino)methylene]-1H-1,2,3-triazolo[4,5-b]pyridinium        3-oxid hexafluorophosphate    -   HBTU: N,N,N′,N′-tetramethyl-O-(1H-benzotriazol-1-yl)uronium        hexafluorophosphate    -   HCl: hydrochloric acid    -   H₄NHCO₃: ammonium bicarbonate    -   Johnphos: (2-biphenyl)di-tert-butylphosphine    -   K₂CO₃: potassium carbonate    -   m-CPBA: 3-chloroperbenzoic acid    -   MeCN: acetonitrile    -   MeOH: methanol    -   MgSO₄: magnesium sulfate    -   min: minutes    -   Na(CN)BH₃: sodium cyanoborohydride    -   Na₂SO₄: sodium sulfate    -   NaHCO₃: sodium bicarbonate    -   NaHSO₄: Sodium hydrogen sulfate    -   NaOH: sodium hydroxide    -   NBS: N-bromosuccinimide    -   NH₂OH: hydroxylamine    -   NH₄Cl: ammonium chloride    -   NH₄HCO₃: ammonium bicarbonate    -   Pd(dppf)Cl₂:        [1,1′-bis(diphenylphosphino)ferrocene]dichloropalladium(II)    -   Pd(dppf)Cl₂·CH₂Cl₂:        [1,1′-bis(diphenylphosphino)ferrocene]dichloropalladium(II)-dichloromethane        adduct    -   Pd(OAc)₂: palladium(II) acetate    -   pet. ether: petroleum ether    -   t-BuOK: potassium tert-butoxide    -   prep-HPLC: preparatory high pressure liquid chromatography    -   prep-SFC: preparatory supercritical fluid chromatography    -   prep-TLC: preparatory thin layer chromatography    -   TFA: trifluoroacetic acid    -   THF: tetrahydrofuran

Example 1—Preparation of4-[(2,2-Dimethyloxan-4-yl)carbonyl]-N-hydroxy-2,3,4,5-tetrahydro-1,4-benzoxazepine-8-carboxamide

Step-1: Methyl 3-bromo-4-(bromomethyl)benzoate

Methyl 3-bromo-4-methylbenzoate (25 g, 109.14 mmol, 1 equiv), NBS (21.5g, 120.80 mmol, 1.11 equiv), benzoyl peroxide (146 mg, 0.57 mmol, 0.01equiv), and CCl₄ (120 mL) were placed in a 250-mL round-bottom flask.The resulting solution was stirred overnight at 85° C. in an oil bath.The resulting mixture was cooled and concentrated under vacuum. Theresidue was purified by silica gel chromatography (EtOAc/pet. ether,1:10) to afford the title compound as a white solid (20 g) and usedwithout further purification.

Step-2: Methyl 3-bromo-4-((2-hydroxyethylamino)methyl)benzoate

Methyl 3-bromo-4-(bromomethyl)benzoate (20 g, 64.94 mmol, 1 equiv),potassium carbonate (26.9 g, 194.63 mmol, 3 equiv), MeCN (100 mL), and2-aminoethan-1-ol (4.76 g, 77.93 mmol, 1.20 equiv) were placed in a250-mL round-bottom flask. The resulting solution was stirred for 2 h at−5° C. The resulting mixture was concentrated under vacuum, washed withwater (50 mL) and EtOAc (50 mL). The organic layer was concentratedunder vacuum and were placed in a 250-mL round-bottom flask.(MeOH/CH₂Cl₂, 1:20) to afford the title compound as a light yellow oil(16 g, 56% yield over 2 steps). MS: (ES, m/z): 288 [M+H]⁺.

Step-3: Methyl 2,3,4,5-tetrahydrobenzo[f][1,4]oxazepine-8-carboxylate

Methyl 3-bromo-4-[[(2-hydroxyethyl)amino]methyl]benzoate (7 g, 24.29mmol, 1 equiv), potassium carbonate (6.6 g, 47.75 mmol, 1.97 equiv), CuI(912 mg, 4.79 mmol, 0.20 equiv), and isopropanol (100 mL) were placed ina 250-mL round-bottom flask. The resulting solution was stirredovernight at 110° C. in an oil bath. The solution was cooled and thesolids were filtered out. The filtrate was concentrated under vacuum andpurified by silica gel chromatography (EtOAc/pet. ether, 1:1) to affordthe title compound as a yellow oil (3 g, 60% yield). ¹H-NMR (300 MHz,CDCl₃) δ (ppm): 7.70-7.68 (t, 2H), 7.26-7.22 (t, 1H), 4.13-4.09 (t, 2H),4.05 (s, 2H), 3.93 (s, 3H), 3.50 (s, 1H), 3.30-3.28 (t, 2H). MS: (ES,m/z): 208 [M+H]⁺.

Step-4: Methyl4-[(2,2-dimethyloxan-4-yl)carbonyl]-2,3,4,5-tetrahydro-1,4-benzoxazepine-8-carboxylate

Into a 25-mL round-bottom flask, was placed2,2-dimethyloxane-4-carboxylic acid (31 mg, 0.19596 mmol, 1 equiv),methyl 2,3,4,5-tetrahydro-1,4-benzoxazepine-8-carboxylate (40 mg,0.19303 mmol, 1 equiv), BOP (130 mg, 0.29647 mmol, 1.50 equiv), Et₃N (30mg, 0.29647 mmol, 1.50 equiv) and DMF (5 mL). The resulting mixture wasstirred for 4 h at 45° C. in an oil bath. The reaction mixture wascooled to 10° C. with a water/ice bath. The reaction was quenched by theaddition of sat. NH₄Cl/H₂O. The resulting solution was extracted withEtOAc (3×30 mL) and dried over anhydrous Na₂SO₄. The solids werefiltered out and the filtrate was concentrated under vacuum. The residuewas purified by silica gel chromatography (EtOAc/pet. ether, 1:5) toafford the title compound as yellow oil (60 mg). MS: (ES, m/z): 348[M+H]⁺.

Step-5:4-[(2,2-Dimethyloxan-4-yl)carbonyl]-N-hydroxy-2,3,4,5-tetrahydro-1,4-benzoxazepine-8-carboxamide

Into a 10-mL round-bottom flask, was placed methyl4-[(2,2-dimethyloxan-4-yl)carbonyl]-2,3,4,5-tetrahydro-1,4-benzoxazepine-8-carboxylate(60 mg, 0.17 mmol, 1 equiv), NH₂OH (50% in water, 343 mg, 30 equiv), aq.1N NaOH (0.346 mL, 2 equiv), and MeOH/THF (1:4, 2 mL). The resultingsolution was stirred for 2 h at 25° C. The pH value of the solution wasadjusted to 6 with HCl (3N). The crude product was purified by Prep-HPLC(Column: XBridge RP C18 OBD, 5 μm, 19×150 mm; Mobile Phase A: Water/10mmol HN₄HCO₃; Mobile Phase B: MeCN; Flow rate: 25 mL/min; Gradient: 5% Bto 47% B in 7 min; Detector, UV 254 nm) to afford the title compound asa white solid (32 mg, 53% yield). ¹H-NMR (400 MHz, DMSO-d₆) δ(ppm):11.18 (s, 1H), 7.37-7.49 (m, 1H), 7.30-7.32 (t, 2H), 4.68-4.89 (m, 1H),4.59-4.61 (d, 1H), 4.20-4.24 (t, 1H), 4-4.05 (m, 1H), 3.92-3.94 (d, 1H),3.62-3.68 (m, 1H), 3.57-3.59 (t, 2H), 3-3.13 (t, 1H), 1.26-1.44 (m, 4H),1.18-1.19 (d, 3H), 1.04-1.12 (t, 3H). MS: (ES, m/z): 349 [M+H]⁺.

Example 2—Preparation of 2-methyl-2-(pyridin-2-yl)propanoic Acid

Step-1: Ethyl 2-methyl-2-(pyridin-2-yl)propanoate

Into a 40-mL vial purged and maintained with an inert atmosphere ofnitrogen, was placed ethyl 2-(pyridin-2-yl)acetate (500 mg, 3.03 mmol, 1equiv), THE (10 mL) and t-BuOK (7.5 mL, 2.50 equiv, 1M). The resultingmixture was stirred for 1 h at 20° C. This was followed by the additionof iodomethane (3.4 g, 23.95 mmol, 8 equiv) dropwise with stirring at 0°C. over 10 min. The mixture was allowed to react for an additional 3 hat 20° C. The reaction was then quenched by the addition of water (20mL). The resulting solution was extracted with EtOAc (3×20 mL), washedwith brine (2×20 mL) and dried over anhydrous Na₂SO₄. The solids werefiltered out. The filtrate was concentrated under vacuum to afford thetitle compound as yellow oil (500 mg, 85% yield). MS: (ES, m/z): 194[M+H]⁺.

Step-2: Methyl-2-(pyridin-2-yl)propanoic Acid

Into a 100-mL round-bottom flask, was placed methyl2-methyl-2-(pyridin-2-yl)propanoate (4 g, 22.32 mmol, 1 equiv), MeOH (50mL), water (15 mL) and NaOH (4.1 g, 102.50 mmol, 5 equiv). The resultingsolution was stirred for 6 h at 20° C. The reaction mixture wasconcentrated under vacuum. The pH value of the solution was adjusted to2 with 2N HCl. The resulting solution was extracted with EtOAc (3×50mL), washed with brine (2×50 mL) and dried over anhydrous Na₂SO₄. Thesolids were filtered out. The filtrate was concentrated under vacuum toafford the title compound as a light brown solid which was used withoutfurther purification. MS: (ES, m/z): 166 [M+H]⁺.

TABLE 1 The following compound was prepared according to the methods ofExamples 1 and 2. Found ¹H-NMR (300 MHz, Structure M + H DMSO-d₆) δ(ppm)

(ES, m/z): 356 [M + H]⁺ 11.13-11.20 (s, 1H), 8.48 (s, 1H), 7.51 (s, 1H),7.27 (m, 5H), 4.24 (s, 2H), 3.27-3.34 (s, 2H), 2.82 (s, 2H), 1.66 (s,6H)

Example 3—Preparation of4-[(2,6-Dimethylphenyl)carbonyl]-N-hydroxy-2,3,4,5-tetrahydro-1,4-benzoxazepine-8-carboxamide

Step-1:4-[(2,6-Dimethylphenyl)carbonyl]-2,3,4,5-tetrahydro-1,4-benzoxazepine-8-carboxylate

Into a 25-mL round-bottom flask, was placed methyl2,3,4,5-tetrahydro-1,4-benzoxazepine-8-carboxylate (72.45 mg, 0.35 mmol,1 equiv) and CH₂Cl₂ (8 mL). This was followed by the addition of DIEA(124.24 mg, 0.96 mmol, 2 equiv) and DMC (97.98 mg, 1.20 equiv) at 0° C.The mixture was stirred for 5 min at room temperature. To the mixturewas added 2,6-dimethylbenzoic acid (100 mg, 0.67 mmol, 1 equiv) dropwisewith stirring. The resulting solution was stirred for 8 h at roomtemperature. The reaction was then quenched by the addition of water (2mL). The resulting solution was extracted with CH₂Cl₂ (3×10 mL), driedover anhydrous Na₂SO₄ and concentrated under vacuum. The residue waspurified by silica gel chromatography (EtOAc/pet. ether, 1:1) to affordthe title compound as a light yellow oil (86 mg, 72% yield). MS: (ES,m/z): 340 [M+H]⁺.

Step-2:4-[(2,6-Dimethylphenyl)carbonyl]-N-hydroxy-2,3,4,5-tetrahydro-1,4-benzoxazepine-8-carboxamide

Into a 25-mL round-bottom flask, was placed methyl4-[(2,6-dimethylphenyl)carbonyl]-2,3,4,5-tetrahydro-1,4-benzoxazepine-8-carboxylate(86 mg, 0.25 mmol, 1 equiv), MeOH/THF (1:4, 1.5 mL), NH₂OH (50% inwater, 418 mg, 12.68 mmol, 50 equiv), aq. 1N NaOH (0.51 mL, 2 equiv).The resulting solution was stirred for 1 h at room temperature. Thereaction mixture was cooled to 0° C. with a water/ice bath. The pH valueof the solution was adjusted to 6 with HCl (6N). The crude product waspurified by Prep-HPLC (Column: HSS C18 OBD, 1.8 μm, 2.1×50 mm; MobilePhase A: Water/0.05% TFA; Mobile Phase B: MeCN/0.05% TFA; Flow rate: 0.7mL/min; Gradient: 5% B to 95% B in 2 min, hold 0.6 min; Detector, UV 254nm) to afford the title compound as a white solid (36 mg, 31% yield).¹H-NMR (400 MHz, DMSO-d₆) δ(ppm): 11.21 (s, 1H), 7.05-7.42 (m, 5H), 4.89(s, 1H), 3.95-4.31 (m, 4H), 3.47-3.49 (m, 1H), 2.04 (s, 4H), 1.86 (s,2H). MS: (ES, m/z): 341 [M+H]⁺.

TABLE 2 The following compounds were prepared according to the method ofExample 3. Found ¹H-NMR (400 MHz, Structure M + H DMSO-d₆) δ(ppm)

(ES, m/z): 323 [M + H]⁺ 11.17 (s, 1H), 7.28-7.39 (m, 3H), 4.62 (s, 2H),4.17-4.20 (m, 2H), 3.96-3.97 (m, 2H), 3.33 (s, 2H), 3.15 (s, 3H), 1.14(s, 6H)

(ES, m/z): 347 [M + H]⁺ 11.17 (m, 1H), 9.04 (s, 1H), 7.21-7.48 (m, 3H),4.78 (s, 1H), 4.58 (s, 1H), 4.11-4.26 (m, 4H), 3.84-3.91 (m, 2H),2.99-3.16 (m, 1H), 180-1.82 (m, 4H), 1.61-1.68 (m, 2H), 1.34-1.36 (m,1H), 1.12-1.15 (m, 1H)

Example 4—Preparation ofN-Hydroxy-4-[[3-(propylamino)-1-benzothiophen-2-yl]carbonyl]-2,3,4,5-tetrahydro-1,4-benzoxazepine-8-carboxamide

Step-1: Methyl4-[[3-(propylamino)-1-benzothiophen-2-yl]carbonyl]-2,3,4,5-tetrahydro-1,4-benzoxazepine-8-carboxylate

A mixture of methyl 2,3,4,5-tetrahydro-1,4-benzoxazepine-8-carboxylate(30 mg, 0.14 mmol, 1 equiv), lithium3-(propylamino)benzo[b]thiophene-2-carboxylate (36 mg, 0.15 mmol, 1equiv), HATU (66 mg, 0.17 mmol, 1.20 equiv), DIEA (57 mg, 0.44 mmol, 3equiv) and DMF (2 mL) was stirred for 2 h at room temperature. Thereaction was then quenched by the addition of water (2 mL). Theresulting solution was extracted with CH₂Cl₂ (5×5 mL) and washed withbrine. The organic layer was dried over anhydrous Na₂SO₄ filtered andconcentrated under vacuum to afford the title compound as yellow oil (15mg, 24% yield) which was used without further purification. MS: (ES,m/z): 425 [M+H]⁺.

Step-2:N-Hydroxy-4-[[3-(propylamino)-1-benzothiophen-2-yl]carbonyl]-2,3,4,5-tetrahydro-1,4-benzoxazepine-8-carboxamide

Into a 8-mL round-bottom flask, was placed methyl4-[[3-(propylamino)-1-benzothiophen-2-yl]carbonyl]-2,3,4,5-tetrahydro-1,4-benzoxazepine-8-carboxylate(13 mg, 0.03 mmol, 1 equiv), MeOH/THF (1:4, 0.5 mL), aq. 1N NaOH (0.062mL, 2 equiv), NH₂OH (50% in water, 243 mg, 120 equiv). The resultingsolution was stirred for 5 h at room temperature. The crude product waspurified by Prep-HPLC (Column: HSS C18 OBD, 1.8 μm, 2.1×50 mm; MobilePhase A: Water/0.05% TFA; Mobile Phase B: MeCN/0.05% TFA; Flow rate: 0.7mL/min; Gradient: 5% B to 95% B in 2 min, hold 0.6 min; Detector, UV 254nm) to afford the title compound as a yellow solid (8 mg, 48% yield).¹H-NMR (400 MHz, DMSO-d₆) δ(ppm): 11.20 (s, 1H), 8.05-8.07 (d, J=8.0 Hz,1H), 7.80-7.82 (d, J=7.2 Hz, 1H), 7.34-7.47 (m, 4H), 7.12-7.15 (m, 1H),4.80 (s, 2H), 4.19 (s, 2H), 3.93 (s, 1H), 2.85-2.88 (t, J₁=7.2 Hz,J₂=14.4 Hz, 2H), 1.35-1.44 (m, 2H), 0.64-0.67 (t, J₁=7.2 Hz, J₂=14.4 Hz,3H). MS: (ES, m/z): 426 [M+H]⁺.

Example 5—Preparation of lithium3-(propylamino)benzo[b]thiophene-2-carboxylate

Step-1: Methyl 3-amino-1-benzothiophene-2-carboxylate

Into a 250-mL round-bottom flask, was placed a solution of2-fluorobenzonitrile (10 g, 82.57 mmol, 1 equiv), methyl2-sulfanylacetate (17.5 g, 164.87 mmol, 2 equiv) in DMF (30 mL). Thiswas followed by the addition of a solution of t-BuOK (18.51 g, 164.96mmol, 2 equiv) in DMF (50 mL) dropwise with stirring at 0° C. Theresulting mixture was stirred for 1 h at room temperature and pouredinto water/ice. The solid was collected by filtration and dried toafford the title compound as a yellow solid (13.5 g) which was usedwithout any purification. MS: (ES, m/z): 208 [M+H]⁺.

Step-2: Methyl 3-(propylamino)-1-benzothiophene-2-carboxylate

Into a 25-mL round-bottom flask, was placed methyl3-amino-1-benzothiophene-2-carboxylate (1 g, 4.83 mmol, 1 equiv), DMF(10 mL), sodium hydride (193 mg, 8.04 mmol, 1 equiv), after stirring for0.5 h, 1-iodopropane (740 mg, 4.35 mmol, 0.90 equiv) was added. Theresulting mixture was stirred for 2 days at room temperature. Thereaction was then quenched by the addition of water (10 mL). Theresulting solution was extracted with CH₂Cl₂ (5×20 mL), washed withbrine (3×20 mL) and dried over anhydrous Na₂SO₄. The solids werefiltered out. The filtrate was concentrated under vacuum. The crudeproduct was purified by silica gel chromatography (Gradient 0-20%EtOAc/pet. ether) to afford the title compound as a yellow solid (0.8 g,66% yield). MS: (ES, m/z): 250 [M+H]⁺.

Step-3: Lithium 3-(propylamino)benzo[b]thiophene-2-carboxylate

Into a 100-mL round-bottom flask, was placed methyl3-(propylamino)-1-benzothiophene-2-carboxylate (200 mg, 0.80 mmol, 1equiv), MeOH/H₂O (10 mL, 1:1) and lithium hydroxide (193 mg, 8.06 mmol,10 equiv). The resulting solution was stirred for 3 h at 70° C. in anoil bath. The reaction mixture was concentrated under vacuum to affordthe title compound as a yellow solid (0.39 g) which was used withoutfurther purification. MS: (ES, m/z): 236 [M−Li+H]⁺.

Example 6—Preparation of lithium3-(dimethylamino)benzo[b]thiophene-2-carboxylate

Step-1: Methyl 3-(dimethylamino)-1-benzothiophene-2-carboxylate

Into a 20-mL sealed tube, was placed methyl3-amino-1-benzothiophene-2-carboxylate (400 mg, 1.93 mmol, 1 equiv), DMF(5 mL), sodium hydride (77 mg, 1.93 mmol, 2 equiv, 60%) and iodomethane(0.8 mL). The resulting solution was stirred for 15 min at 150° C. in amicrowave reactor. The reaction was then quenched by the addition ofwater (10 mL). The resulting solution was extracted with CH₂Cl₂ (3×5 mL)and dried over anhydrous Na₂SO₄. The solids were filtered out. Thefiltrate was concentrated under vacuum and purified by silica gelchromatography (EtOAc/pet. ether, 1:1) to afford the title compound as ayellow oil (0.13 g, 29% yield). MS: (ES, m/z): 236 [M+H]⁺.

Step-2: Lithium 3-(dimethylamino)benzo[b]thiophene-2-carboxylate

Into a 25-mL round-bottom flask, was placed methyl3-(dimethylamino)-1-benzothiophene-2-carboxylate (130 mg, 0.55 mmol, 1equiv), LiOH (130 mg, 5.43 mmol, 10 equiv) and MeOH/H₂O (5 mL/2 mL). Themixture was stirred for 5 h at 70° C. in an oil bath. The reactionmixture was concentrated under vacuum to afford the title compound as ayellow solid (0.1 g) which was used without purification. MS: (ES, m/z):222 [M-Li+H]⁺.

Example 7—Preparation of Sodium2-[(tert-butoxy)carbonyl]-5-oxa-2-azaspiro[3.4]octane-7-carboxylic Acid

Step-1: 2-tert-Butyl 7-methyl5-oxa-2-azaspiro[3.4]octane-2,7-dicarboxylate

Into a 25-mL round-bottom flask, was placed methyl5-oxa-2-azaspiro[3.4]octane-7-carboxylate (248 mg, 1.45 mmol, 1 equiv),Et₃N (439.44 mg, 4.34 mmol, 3 equiv), di-tert-butyl-dicarboxylate (316.2mg, 3.17 mmol, 1 equiv) and CH₂Cl₂ (5 mL). The resulting solution wasstirred overnight at room temperature and then concentrated undervacuum. The residue was purified by silica gel chromatography(MeOH/CH₂Cl₂, 1:20) to afford the title compound as a light yellow solid(205 mg, 52% yield). MS: (ES, m/z): 216 [M+H]⁺.

Step-2: Sodium2-[(tert-butoxy)carbonyl]-5-oxa-2-azaspiro[3.4]octane-7-carboxylic Acid

Into a 50-mL round-bottom flask, was placed 2-tert-butyl 7-methyl5-oxa-2-azaspiro[3.4]octane-2,7-dicarboxylate (100 mg, 0.37 mmol, 1equiv), THF/H₂O (2 mL/2 mL), and NaOH (0.74 mL, 2 equiv, 1N). Theresulting solution was stirred for 3 h at room temperature. The reactionmixture was concentrated under vacuum to afford the title compound as ayellow solid (110 mg) which was used without further purification. MS:(ES, m/z): 258 [M+H−Na⁺]⁺.

Example 8—Preparation of2-(tert-butoxycarbonyl)-5-thia-2-azaspiro[3.4]octane-7-carboxylic Acid5,5-dioxide

Step-1: tert-Butyl7-[[(4-methylbenzene)sulfonyl]oxy]-5-thia-2-azaspiro[3.4]octane-2-carboxylate

Into a 250-mL round-bottom flask purged and maintained with an inertatmosphere of nitrogen, was placed tert-butyl7-hydroxy-5-thia-2-azaspiro[3.4]octane-2-carboxylate (8 g, 32.61 mmol, 1equiv), m-toluenesulfonyl chloride (6.8 g, 35.67 mmol, 1.10 equiv),CH₂Cl₂ (100 mL) and 4-dimethylaminopyridine (7.9 g, 64.66 mmol, 2equiv). The solution was stirred for 4 h at 20° C. The solution wasdiluted with CH₂Cl₂ (100 mL) and washed with 0.5M HCl (2×50 mL) andbrine (3×50 mL). The mixture was dried over anhydrous Na₂SO₄. The solidswere filtered out. The filtrate was concentrated under vacuum to affordthe title compound as a yellow solid (8.5 g, 65% yield) which was usedwithout further purification. MS: (ES, m/z): 400 [M+H]⁺.

Step-2: tert-Butyl 7-cyano-5-thia-2-azaspiro[3.4]octane-2-carboxylate

Into a 250-mL round-bottom flask purged and maintained with an inertatmosphere of nitrogen, was placed tert-butyl7-[[(4-methylbenzene)sulfonyl]oxy]-5-thia-2-azaspiro[3.4]octane-2-carboxylate(8.5 g, 21.28 mmol, 1 equiv), DMSO (100 mL) and potassium cyanide (2 g,30.71 mmol, 1.50 equiv). The resulting mixture was stirred for 15 h at90° C. in an oil bath. The reaction was then quenched by the addition of200 mL of water/ice. The resulting solution was extracted with EtOAc(4×100 mL), washed with brine (2×100 mL) and dried over anhydrousNa₂SO₄. The solids were filtered out. The filtrate was concentratedunder vacuum. The residue was purified by silica gel chromatography(EtOAc/pet. ether, 1:5) to afford the title compound as colorless oil (3g, 55% yield). MS: (ES, m/z): 255 [M+H]⁺.

Step-3: 5-Thia-2-azaspiro[3.4]octane-7-carboxylic Acid Hydrochloride

Into a 50-mL round-bottom flask, was placed tert-butyl7-cyano-5-thia-2-azaspiro[3.4]octane-2-carboxylate (3 g, 11.79 mmol, 1equiv) and conc. HCl (30 mL). The above solution was stirred for 12 h at60° C. in an oil bath. The resulting mixture was concentrated undervacuum to afford the title compound as light yellow oil (2.8 g) whichwas used without further purification. MS: (ES, m/z): 174 [M+H]⁺.

Step-4: Methyl 5-thia-2-azaspiro[3.4]octane-7-carboxylate Hydrochloride

Into a 100-mL round-bottom flask purged and maintained with an inertatmosphere of nitrogen, was placed MeOH (50 mL). This was followed bythe addition of thionyl chloride (2.37 g, 20.08 mmol, 1.50 equiv)dropwise with stirring at 0° C. over 10 min. After the addition wasfinished the solution was stirred for an additional 30 min at 20° C. Tothis was added a solution of 5-thia-2-azaspiro[3.4]octane-7-carboxylicacid hydrochloride (2.8 g, 13.35 mmol, 1 equiv) in MeOH (5 mL) dropwiseat 0° C. over 10 min. The resulting solution was stirred for anadditional 2 h at 70° C. in an oil bath. The reaction mixture wasconcentrated under vacuum to afford the title compound as yellow oil(2.5 g, 84% yield) which was used without further purification. MS: (ES,m/z): 188 [M+H]⁺.

Step-5: 2-tert-Butyl 7-methyl5-thia-2-azaspiro[3.4]octane-2,7-dicarboxylate

Into a 100-mL round-bottom flask, was placed methyl5-thia-2-azaspiro[3.4]octane-7-carboxylate (2.5 g, 13.35 mmol, 1 equiv),di-tert-butyl dicarbonate (2.9 g, 13.29 mmol, 1.20 equiv), CH₂Cl₂ (50mL), and Et₃N (3.4 g, 33.60 mmol, 3 equiv). The above mixture wasstirred for 3 h at 20° C. and then diluted with CH₂Cl₂ (100 mL). Themixture was washed with brine (3×50 mL) and dried over anhydrous Na₂SO₄.The solids were filtered out and the filtrate was concentrated undervacuum. The residue was purified by silica gel chromatography(EtOAc/pet. ether, 8:1) to afford the title compound as a white solid(2.6 g, 68% yield). MS: (ES, m/z): 288 [M+H]⁺.

Step-6: 2-(tert-Butyl) 7-methyl5-thia-2-azaspiro[3.4]octane-2,7-dicarboxylate 5,5-dioxide

Into a 100-mL round-bottom flask purged and maintained with an inertatmosphere of nitrogen, was placed 2-tert-butyl 7-methyl5-thia-2-azaspiro[3.4]octane-2,7-dicarboxylate (2.6 g, 9.05 mmol, 1equiv), CH₂Cl₂ (50 mL) and m-CPBA (4.6 g, 26.66 mmol, 3 equiv). Theresulting solution was stirred for 4 h at 20° C. The reaction mixturewas diluted with CH₂Cl₂ (100 mL), washed with sat. aq. NaHCO₃ solution(50 mL), sat. aq. NaHSO₄ solution (50 mL) and brine (2×50 mL). Theorganic layer was dried over anhydrous Na₂SO₄, filtered and concentratedunder vacuum. The residue was purified by silica gel chromatography(EtOAc/pet. ether, 1:2) to afford the title compound as a white solid(2.2 g, 76% yield). MS: (ES, m/z): 320 [M+H]⁺.

Step-7:2-(tert-Butoxycarbonyl)-5-thia-2-azaspiro[3.4]octane-7-carboxylic acid5,5-dioxide

Into a 25-mL round-bottom flask, was placed 2-(tert-Butyl) 7-methyl5-thia-2-azaspiro[3.4]octane-2,7-dicarboxylate 5,5-dioxide (500 mg, 1.57mmol, 1 equiv), THF/H₂O (10 mL, 1:1) and NaOH (125.4 mg, 3.14 mmol, 2equiv). The resulting solution was stirred for 4 h at room temperature.The pH value of the solution was adjusted to 6 with 1N HCl thenconcentrated under vacuum. The residue was washed with CH₂Cl₂ (3×10 mL),and the organic layer was concentrated under vacuum to afford the titlecompound as a light yellow solid (560 mg) which was used without furtherpurification. MS: (ES, m/z): 206 [M+H-Boc]⁺.

TABLE 3 The following compounds were prepared according to the methodsof Examples 4 through 8. Found ¹H-NMR (400 MHz, Structure M + H DMSO-d₆)δ(ppm)

(ES, m/z): 412 [M + H]⁺ 11.18 (s, 1H), 7.90-7.91 (d, J = 2.4 Hz, 1H)7.88-7.89 (d, J = 3.2 Hz, 1H), 7.33-7.44 (m, 5H), 4.83 (s, 2H),3.91-4.23 (m, 4H), 2.67-2.77 (m, 6H)

(ES, m/z): 477 [M + H]⁺ 11.17-11.19 (m, 1H), 8.40-9.35 (br, 1H),7.30-7.54 (m, 3H), 4.60-4.73 (m, 2H), 3.44-4.17 (m, 11H), 2.09-2.04 (m,2H), 1.34 (s, 9H)

(ES, m/z): 496 [M + H]⁺ 11.18-11.21 (m, 1H), 9.06 (br, 1H), 7.33-7.56(m, 3H), 4.61-4.78 (m, 2H), 3.84-4.16 (m, 8H), 3.26-3.38 (m, 3H),2.40-2.57 (m, 1H), 2.20-2.28 (m, 1H), 1.37 (s, 9H)

Example 9—Preparation of(S)—N-Hydroxy-4-(tetrahydro-2H-pyran-3-carbonyl)-2,3,4,5-tetrahydrobenzo[f][1,4]oxazepine-8-carboxamideand(R)—N-Hydroxy-4-(tetrahydro-2H-pyran-3-carbonyl)-2,3,4,5-tetrahydrobenzo[f][1,4]oxazepine-8-carboxamide

Step-1: methyl(S)-4-(tetrahydro-2H-pyran-3-carbonyl)-2,3,4,5-tetrahydrobenzo[f][1,4]oxazepine-8-carboxylateand methyl(R)-4-(tetrahydro-2H-pyran-3-carbonyl)-2,3,4,5-tetrahydrobenzo[f][1,4]oxazepine-8-carboxylate

A mixture of methyl 2,3,4,5-tetrahydro-1,4-benzoxazepine-8-carboxylate(250 mg, 1.21 mmol, 1 equiv), tetrahydro-2H-pyran-3-carboxylic acid (157mg, 1.21 mmol, 1 equiv), DIEA (469 mg, 3.63 mmol, 3 equiv), and HATU(552 mg, 1.45 mmol, 1.2 equiv) and in DMF (4 mL) was stirred overnightat room temperature. The reaction was then quenched by the addition ofwater (2 mL). The resulting solution was extracted with CH₂Cl₂ (3×10 mL)and washed with brine. The organic layer was dried over anhydrousNa₂SO₄, filtered, and concentrated under vacuum. The crude racemicmixture was purified by chiral Prep-HPLC (Column: Chiralpak IA 2×25 cm,5 μm; Mobile Phase A: hexanes; Mobile Phase B: EtOH; Flow rate: 20mL/min; Gradient: 30% B for 26 min; Detector, UV 254, 220 nm) to affordsingle isomers of the title compound. The first eluting isomer wasisolated as a white solid (55 mg, 14% yield). MS: (ES, m/z): 320 [M+H]⁺.The second eluting isomer was isolated as a white solid (55 mg, 14%yield). MS: (ES, m/z): 320 [M+H]⁺.

Step-2:(S)—N-Hydroxy-4-(tetrahydro-2H-pyran-3-carbonyl)-2,3,4,5-tetrahydrobenzo[f][1,4]oxazepine-8-carboxamideand(R)—N-Hydroxy-4-(tetrahydro-2H-pyran-3-carbonyl)-2,3,4,5-tetrahydrobenzo[f][1,4]oxazepine-8-carboxamide

A solution of methyl4-(tetrahydro-2H-pyran-3-carbonyl)-2,3,4,5-tetrahydrobenzo[f][1,4]oxazepine-8-carboxylate(55 mg, 0.17 mmol, 1 equiv) in MeOH/THF (1:4, 2 mL), aq. 1N NaOH (0.35mL, 2 equiv), NH₂OH (50% in water, 569 mg, 50 equiv) was stirred for 1 hat room temperature. The reaction mixture was cooled to 0° C. with anice-water bath. The pH value of the solution was adjusted to 6 with aq.6N HCl. The crude product was purified by Prep-HPLC (Column: HSS C18OBD, 1.8 μm, 2.1×50 mm; Mobile Phase A: Water/0.05% TFA; Mobile Phase B:MeCN/0.05% TFA; Flow rate: 0.7 mL/min; Gradient: 5% B to 95% B in 2 min,hold 0.6 min; Detector, UV 254 nm). Reaction with the first elutingisomer from Step 1 afforded the title compound as a pink solid (15.2 mg,28% yield). ¹H-NMR (400 MHz, DMSO-d₆) δ(ppm): 11.17 (s, 1H), 9.00 (br,1H), 7.26-7.52 (m, 3H), 4.76 (s, 1H), 4.57 (s, 1H), 4.11-4.18 (m, 2H),3.31-3.91 (m, 4H), 3.20-3.29 (m, 2H), 2.80-2.98 (m, 1H), 1.44-1.79 (m,4H). MS: (ES, m/z): 321 [M+H]⁺. Reaction with the second eluting isomerfrom Step 1 afforded the title compound as a pink solid (15.8 mg, 29%yield). ¹H-NMR (400 MHz, DMSO-d₆) δ(ppm): 11.17 (s, 1H), 9.00 (br, 1H),7.26-7.52 (m, 3H), 4.76 (s, 1H), 4.57 (s, 1H), 4.06-4.18 (m, 2H),3.56-3.91 (m, 4H), 3.20-3.31 (m, 2H), 2.82-2.98 (m, 1H), 1.43-1.79 (m,4H). MS: (ES, m/z): 321 [M+H]⁺.

TABLE 4 The following compounds were prepared according to the method ofExample 9. Found ¹H-NMR (400 MHz, DMSO-d₆) Structure M + H δ(ppm)

(ES, m/z): 307 [M + H]⁺ 11.18-11.16 (m, 1H), 9.01 (br, 1H), 7.53-7.51(m, 1H), 7.42-7.38 (m, 1H), 4.75 (s, 1H), 4.61 (s, 1H), 4.18-4.12 (m,2H), 3.92-3.78 (m, 3H), 3.68-3.60 (m, 3H), 3.53-3.50 (m, 1H), 3.36-3.30(m, 1H), 2.01-1.84 (m, 2H)

(ES, m/z): 307 [M + H]⁺ 11.18-11.16 (m, 1H), 9.01 (br, 1H), 7.53-7.51(m, 1H), 7.42-7.38 (m, 1H), 4.75 (s, 1H), 4.61 (s, 1H), 4.18-4.12 (m,2H), 3.92-3.78 (m, 3H), 3.68-3.60 (m, 3H), 3.53-3.50 (m, 1H), 3.36-3.30(m, 1H), 2.01-1.84 (m, 2H) The compounds of Table 4 were separated atthe methyl ester intermediate by Prep-HPLC (Column: Chiralpak IA-3 0.46× 5 cm, 3 μm; Mobile Phase A: hexanes; Mobile Phase B: EtOH; Flow rate:20 mL/min; Gradient: 50% B for 25 min; Detector, UV 254, 220 nm)

Example 10—Preparation ofN-hydroxy-4-(1-methoxycyclopropane-1-carbonyl)-2,3,4,5-tetrahydrobenzo[f][1,4]oxazepine-8-carboxamide

Step-1: Methyl4-(1-methoxycyclopropane-1-carbonyl)-2,3,4,5-tetrahydrobenzo[f][1,4]oxazepine-8-carboxylate

To a solution of 1-methoxycyclopropane-1-carboxylic acid (50 mg, 0.43mmol, 1 equiv) in DMF (2 mL) was added HATU (197 mg, 0.52 mmol, 1.2equiv), in portions at 0° C., followed by methyl2,3,4,5-tetrahydro-1,4-benzoxazepine-8-carboxylate (138 mg, 0.43 mmol, 1equiv) and DIEA (167 mg, 1.29 mmol, 3 equiv). The resulting solution wasstirred overnight at room temperature. The reaction was then quenched bythe addition of water (5 mL). The resulting solution was extracted withEtOAc (3×10 mL). The organic layer was washed with water (10 mL) andwith brine (10 mL), dried over anhydrous Na₂SO₄, filtered, andconcentrated under vacuum. The residue was purified by silica gelchromatography (EtOAc/pet. ether, 1:1) to afford the title compound as alight yellow oil (20 mg, 15% yield). MS: (ES, m/z): 306 [M+H]⁺.

Step-2:N-Hydroxy-4-(1-methoxycyclopropane-1-carbonyl)-2,3,4,5-tetrahydrobenzo[f][1,4]oxazepine-8-carboxamide

To a solution of methyl4-(1-methoxycyclopropane-1-carbonyl)-2,3,4,5-tetrahydrobenzo[f][1,4]oxazepine-8-carboxylate(20 mg, 0.07 mmol, 1 equiv) in MeOH/THF (1:4, 1 mL) was addedsimultaneously aq. 6N NaOH (0.13 mL, 2 equiv), NH₂OH (50% in water, 0.12mL, 50 equiv). The resulting solution was stirred for 1 h at roomtemperature. The crude product was purified by Prep-HPLC (Column SunfireC18 5 μm, 19×100 mm; Mobile Phase A: Water/0.05% TFA; Mobile Phase B:MeCN; Flow rate: 25 mL/min; Gradient: 6% B to 48% B in 8 min, hold 0.6min; Detector, UV 254, 220 nm) to afforded the title compound as anorange solid (7.9 mg, 39% yield). ¹H-NMR (400 MHz, DMSO-d₆) δ(ppm):11.17 (br, 1H), 9.01 (br, 1H), 7.47-7.25 (m, 3H), 5.03-4.53 (m, 2H),4.66-4.29 (m, 3H), 3.95-3.78 (m, 1H), 3.20-2.80 (m, 3H), 0.98-0.75 (m,4H). MS: (ES, m/z): 307 [M+H]⁺.

TABLE 5 The following compounds were prepared according to the method ofExample 10. Found ¹H-NMR (400 MHz, Structure M + H DMSO-d₆) δ(ppm)

(ES, m/z): 335 [M + H]⁺ 11.15 (br, 1H), 9.03 (br, 1H), 7.39-7.34 (m,2H), 7.28 (s, 1H), 4.64 (s, 2H), 4.20- 4.18 (m, 2H), 3.98-3.95 (m, 2H),3.59-3.54 (m, 2H), 3.41-3.32 (m, 2H), 1.97-1.93 (m, 2H), 1.47-1.44 (m,2H), 1.21 (s, 3H)

(ES, m/z): 321 [M + H]⁺ 11.18 (br, 1H), 9.03 (br, 1H), 7.46-7.27 (m,3H), 4.78-4.60 (m, 3.5H), 4.45-4.35 (m, 0.5H), 4.36-4.21 (m, 3H),4.22-4.13 (m, 1.5H), 3.92-3.83 (m, 0.5H), 3.46-3.37 (m, 1H), 2.02-1.87(m, 2H), 0.81-0.66 (m, 3H)

(ES, m/z): 316 [M + H]⁺ 11.20 (s, 1H), 7.42-7.41 (m, 1H), 7.40-7.39 (m,1H), 7.33-7.23 (br, 1H), 6.91 (s, 1H), 6.23 (s, 1H), 6.04- 6.02 (m, 1H),4.78 (s, 2H), 4.26-4.25 (m, 2H), 4.00- 3.99 (m, 2H), 3.58 (s, 3H)

(ES, m/z): 366 [M + H]⁺ 11.28 (br, 1H), 8.79- 8.467.72-7.69 (m, 1H),7.61-7.59 (m, 2H), 7.49-43 (m, 2H), 7.28-7.20 (m, 1H), 7.12-7.09 (m,1H), 6.92-6.46 (m, 1H), 5.04-5.00 (m, 2H), 4.65-4.62 (m, 2H) 4.05-3.90(m, 2H), 3.64 (s, 3H)

(ES, m/z): 463 [M + H]⁺ 11.19 (br, 1H), 9.06-9.04 (br, 1H), 7.95-7.87(m, 3H), 7.48-7.28 (m, 3H), 4.83 (s, 1H), 4.64 (s, 1H), 4.24-4.23 (m,1H), 4.16-4.14 (m, 1H), 4.05 (s, 1H), 4.01-3.98 (m, 2H), 3.91-3.90 (m,1H)

(ES, m/z): 449 [M + H]⁺ 11.20 (br, 1H), 9.07 (br, 1H), 8.27-8.22 (m,1H), 8.15 (s, 1H), 7.83 (s, 1H), 7.44-7.32, 6.82-6.80 (m, 3H), 4.82 (s,1H), 4.49 (s, 1H), 4.35 (m, 1H), 4.18 (m, 1H), 4.02 (m, 1H), 3.73 (m,1H)

(ES, m/z): 317 [M + H]⁺ 11.17 (br, 1H), 9.04 (br, 1H), 7.76-7.74 (m,1H), 7.42-7.22 (m, 3H), 6.52-6.51 (d, J = 4.0 Hz, 1H), 5.17 (s, 1H),4.74 (m, 1H), 4.33-4.32 (m, 1H), 4.20-4.17 (m, 2H), 3.99-3.96 (m, 2H),3.89-3.86 (m, 2H)

(ES, m/z): 369 [M + H]⁺ 11.21 (br, 1H), 9.05 (br, 1H), 7.56-7.24 (m,3H), 6.74-6.72 (d, J = 8.0 Hz, 2H), 4.84 (s, 1H), 4.62 (s, 1H),4.23-4.22 (m, 1H), 4.15-4.13 (m, 1H), 4.05-4.04 (m, 1H), 3.88-3.87 (m,1H), 3.66-3.63 (m, 2H), 2.17-2.16 (m, 3H), 2.01 (m, 2H), 1.85 (m, 4H)

Example 11—Preparation ofN-hydroxy-4-pivaloyl-2,3,4,5-tetrahydrobenzo[f][114]oxazepine-8-carboxamide

Step-1: Methyl4-pivaloyl-2,3,4,5-tetrahydrobenzo[f][1,4]oxazepine-8-carboxylate

Into a 25-mL round-bottom flask, was placed a solution of methyl2,3,4,5-tetrahydro-1,4-benzoxazepine-8-carboxylate (80 mg, 0.39 mmol, 1equiv) in CH₂Cl₂ (2 mL), and Et₃N (118 mg, 1.17 mmol, 3 equiv). This wasfollowed by the addition of 2,2-dimethylpropanoyl chloride (46.6 mg,0.39 mmol, 1 equiv) dropwise with stirring at 0° C. The resultingsolution was stirred for 30 min at room temperature. The reaction wasthen quenched by the addition of water (2 mL). The mixture was extractedwith CH₂Cl₂ (3×10 mL). The organic layer was dried over anhydrousNa₂SO₄, filtered, and concentrated under vacuum. The residue waspurified by silica gel chromatography (EtOAc/pet. ether, 1:1) to affordthe title compound as a light yellow solid (90 mg, 80% yield). MS: (ES,m/z): 292 [M+H]⁺.

Step-2: N-hydroxy-4-pivaloyl-2,3,4,5-tetrahydrobenzo[f][1,4]oxazepine-8-carboxamide

Into a 25-mL round-bottom flask, was placed a solution of methyl4-pivaloyl-2,3,4,5-tetrahydrobenzo[f][1,4]oxazepine-8-carboxylate (90mg, 0.31 mmol, 1 equiv) in THF/MeOH (4:1, 2 mL), aq. 1N NaOH (0.62 mL, 2equiv) and NH₂OH (50% in water, 510 mg, 15.46 mmol, 50 equiv). Theresulting solution was stirred for 1 h at room temperature. The pH valueof the solution was adjusted to 6 with aq. 6N HCl at 0°. The crudeproduct was purified by Prep-HPLC (Column: HSS C18 OBD, 1.8 μm, 2.1×50mm; Mobile Phase A: Water/0.05% TFA; Mobile Phase B: MeCN/0.05% TFA;Flow rate: 0.7 mL/min; Gradient: 5% B to 95% B in 2 min, hold 0.6 min;Detector, UV 254 nm) to afford the title compound as a white solid (34.2mg, 27% yield). ¹H-NMR (400 MHz, DMSO-d₆) δ(ppm): 11.17 (s, 1H), 9.03(s, 1H), 7.29-7.39 (m, 3H), 4.61 (s, 2H), 4.18-4.20 (t, J₁=4.8 HZ,J₂=9.2 Hz, 2H), 3.97-3.99 (d, J=5.2 Hz, 2H), 1.16 (s, 9H). MS: (ES,m/z): 293 [M+H]⁺.

TABLE 6 The following compounds were prepared according to the method ofExample 11. Found Structure M + H ¹H-NMR (400 MHz, DMSO-d₆) δ(ppm)

(ES, m/z): 313 [M + H]⁺ 11.20 (s, 1H), 7.13-7.45 (m, 8H), 4.79 (s, 1H),4.51 (s, 1H), 4.15-4.29 (m, 3H), 3.99 (s, 1H)

(ES, m/z): 251 [M + H]⁺ 11.16-11.18 (d, 1H), 10.10 (s, 1H), 9.03 (s,1H), 7.29-7.44 (m, 3H), 4.57-4.64 (d, 2H), 4.15-4.17 (t, 1H), 4.07-4.09(t, 1H), 3.43 (m, 2H), 1.98-2.03 (m, 3H)

Example 12—Preparation of4-formyl-N-hydroxy-2,3,4,5-tetrahydrobenzo[f][1,4]oxazepine-8-carboxamide2,2,2-trifluoroacetate

Step-1: Methyl4-formyl-2,3,4,5-tetrahydro-1,4-benzoxazepine-8-carboxamide

Into a 8-mL vial, was placed methyl2,3,4,5-tetrahydro-1,4-benzoxazepine-8-carboxylate (150 mg, 0.47 mmol, 1equiv) and ethyl formate (2 mL). The resulting solution was stirred for16 h at 60° C. in an oil bath. The resulting mixture was concentratedunder vacuum to afford the title compound as yellow oil which was usedwithout further purification. MS: (ES, m/z): 236 [M+H]⁺.

Step-2:4-Formyl-N-hydroxy-2,3,4,5-tetrahydrobenzo[f][1,4]oxazepine-8-carboxamide

Into a 8-mL vial, was placed methyl4-formyl-2,3,4,5-tetrahydro-1,4-benzoxazepine-8-carboxylate (100 mg,0.43 mmol, 1 equiv) in THF/MeOH (4:1, 2 mL), aq. 1N NaOH (0.85 mL, 0.85mmol, 2 equiv), and NH₂OH (50% in water, 0.85 mL, 12.72 mmol, 30 equiv).The resulting solution was stirred for 2 h at room temperature. Thecrude product was purified by Prep-HPLC (Column: XBridge RP C18 OBD, 5μm, 19×150 mm; Mobile Phase A: Water/0.05% TFA; Mobile Phase B: MeCN;Flow rate: 25 mL/min; Gradient: 4% B to 58% B in 7 min; Detector, UV254, 220 nm) to afford the title compound as a pink solid (15 mg, 10%yield). ¹H-NMR (400 MHz, DMSO-d₆) δ(ppm): 11.19 (s, 1H), 10-10.11 (s,1H), 9.03 (s, 1H), 8.20 (s, 0.4H), 8.04 (s, 0.6H), 7.33-7.43 (m, 3H),4.61-4.64 (d, 0.9H), 4.52-4.55 (d, 1.2H), 4.10-4.14 (m, 2H), 3.76-3.78(m, 2H). MS: (ES, m/z): 237 [M+H]⁺.

Example 13—Preparation of tert-Butyl3-[8-(hydroxycarbamoyl)-2,3,4,5-tetrahydro-1,4-benzoxazepine-4-carbonyl]-3H-spiro[2-benzofuran-1,4′-piperidine]-1′-carboxylateandN-hydroxy-4-(3H-spiro[isobenzofuran-1,4′-piperidine]-3-carbonyl)-2,3,4,5-tetrahydrobenzo[f][1,4]oxazepine-8-carboxamide

Step-1: tert-Butyl3-(8-(methoxycarbonyl)-2,3,4,5-tetrahydrobenzo[f][1,4]oxazepine-4-carbonyl)-3H-spiro[isobenzofuran-1,4′-piperidine]-1′-carboxylate

Into a 20 ml scintillation vial, was placed methyl2,3,4,5-tetrahydrobenzo[f][1,4]oxazepine-8-carboxylate (21 mg, 0.1mmol),1′-(tert-butoxycarbonyl)-3H-spiro[isobenzofuran-1,4′-piperidine]-3-carboxylicacid (33 mg, 0.1 mmol) and chloroform (3 mL). This was followed by theaddition of DIEA (0.052 ml, 0.3 mmol) and DMC (20 mg, 0.12 mmol) atambient temperature. The resulting solution was stirred for 3 h at roomtemperature. The reaction was then diluted with CH₂Cl₂ (10 mL) andwashed with 75% aqueous brine (20 mL). The resulting solution was passedthrough an Isolute© phase separator, then concentrated to dryness. Theresidue gave a quantitative yield of the title compound as an yellowsemi-solid which was used without further purification. MS: (ES, m/z):523 [M+H]⁺.

Step-2: tert-Butyl3-(8-(hydroxycarbamoyl)-2,3,4,5-tetrahydrobenzo[f][1,4]oxazepine-4-carbonyl)-3H-spiro[isobenzofuran-1,4′-piperidine]-1′-carboxylate

In a 20-ml scintillation vial, tert-butyl3-(8-(methoxycarbonyl)-2,3,4,5-tetrahydrobenzo[f][1,4]oxazepine-4-carbonyl)-3H-spiro[isobenzofuran-1,4′-piperidine]-1′-carboxylate(52 mg, 0.1 mmol) was dissolved in MeOH/THF (1:1, 1 mL), NH₂OH (50% inwater, 0.5 ml, 7.57 mmol), and aq. 1N NaOH (0.5 mL, 0.5 mmol). Theresulting solution was stirred for 2 hours at ambient temperature, thenconcentrated to dryness. The crude product was purified by Prep-HPLC(Column: XBridge RP C18 OBD, 5 μm, 19×150 mm; Mobile Phase A:Water/0.05% formic acid; Mobile Phase B: MeCN/0.05% formic acid; Flowrate: 23 mL/min; Gradient: 0% B to 35% B in 8 min; Detector, UV 254, 220nm) to afford the title compound. MS: (ES, m/z): 524 [M+H]⁺.

Step-3:N-hydroxy-4-(3H-spiro[isobenzofuran-1,4′-piperidine]-3-carbonyl)-2,3,4,5-tetrahydrobenzo[f][1,4]oxazepine-8-carboxamide

In a 20-ml scintillation vial, tert-butyl3-(8-(hydroxycarbamoyl)-2,3,4,5-tetrahydrobenzo[f][1,4]oxazepine-4-carbonyl)-3H-spiro[isobenzofuran-1,4′-piperidine]-1′-carboxylate(40 mg, 0.19 mmol) was taken up in CH₂Cl₂ (2 mL) then TFA (1 mL) wasadded. The resulting solution was stirred at ambient temperature for 1h, then concentrated to dryness. The crude product was purified byPrep-HPLC (Column: XBridge RP C18 OBD, 5 μm, 19×150 mm; Mobile Phase A:Water/0.1% formic acid; Mobile Phase B: MeCN/0.1% formic acid; Flowrate: 23 mL/min; Gradient: 0% B to 35% B in 8 min; Detector, UV 254, 220nm) to afford the title compound as the formic acid salt as a whitesolid (9 mg, 28% yield). ¹H-NMR (400 MHz, DMSO-d₆) δ(ppm): 6.93-7.63 (m,7H) 5.97-6.30 (m, 1H) 4.46-4.81 (m, 1H) 3.92-4.45 (m, 4H) 2.57-3.18 (m,6H) 1.49-2.05 (m, 4H). MS: (ES, m/z): 424 [M+H]⁺.

TABLE 7 The following compounds were prepared according to the method ofExample 13. Found ¹H-NMR (400 MHz, Structure M + H DMSO-d₆) δ(ppm)

(ES, m/z): 374 [M + H]⁺

(ES, m/z): 474 [M + H]⁺ 10.88-11.41 (m, 1 H) 8.88-9.27 (m, 1 H)7.24-7.55 (m, 3 H) 4.53-4.79 (m, 2 H) 3.99-4.27 (m, 2 H) 3.87 (br d, J =15.54 Hz, 1 H) 3.24 (br s, 3 H) 2.96 (br d, J = 8.79 Hz, 2 H) 1.66 (q, J= 6.94 Hz, 2 H) 1.34-1.49 (m, 18 H)

(ES, m/z): 374 [M + H]⁺

(ES, m/z): 460 [M + H]⁺ 11.16 (br s, 1 H) 9.02 (br s, 1 H) 7.19-7.58 (m,3 H) 4.73 (br s, 1 H) 4.03 (br s, 3 H) 3.65 (s, 1 H) 2.98- 3.28 (m, 6 H)1.67 (br d, J = 9.97 Hz, 5 H) 1.47-1.60 (m, 3 H) 1.28-1.46 (m, 9 H)

(ES, m/z): 360 [M + H]⁺

(ES, m/z): 524 [M + H]⁺

(ES, m/z): 424 [M + H]⁺ 8.31 (s, 1 H) 7.21-7.60 (m, 4 H) 7.15 (td, J =7.33, 3.52 Hz, 1 H) 6.89 (td, J = 7.33, 3.52 Hz, 1 H) 6.72- 6.83 (m, 1H) 5.53-5.60 (m, 1 H) 4.65-5.01 (m, 2 H) 4.19-4.58 (m, 4 H) 3.87-4.19(m, 4 H) 2.80- 3.26 (m, 4 H) 1.74-2.05 (m, 4 H)

(ES, m/z): 522 [M + H]⁺

(ES, m/z): 422 [M + H]⁺ 8.40 (br s, 1 H) 6.69-7.62 (m, 7 H) 4.54-5.03(m, 2 H) 3.98-4.31 (m, 3 H) 3.03-3.23 (m, 3 H) 2.62-3 (m, 3 H) 2.20-2.44(m, 1 H) 1.83-2.18 (m, 2 H) 1.49-1.78 (m, 3 H)

(ES, m/z): 488 [M + H]⁺ 11.17 (br s, 1 H) 9.05 (br s, 1 H) 7.19-7.51 (m,3 H) 4.72 (s, 1 H) 4.58 (s, 1 H) 4.03-4.25 (m, 2 H) 3.86 (br d, J =14.07 Hz, 2 H) 3.18-3.31 (m, 4 H) 2.71 (br d, J = 12.31 Hz, 1 H) 1.61(br d, J = 10.55 Hz, 2 H) 1.32-1.51 (m, 14 H) 1.06-1.27 (m, 5 H)

(ES, m/z): 474 [M + H]⁺ 11.15 (br s, 1 H) 9.06 (br s, 1 H) 7.28-7.51 (m,3 H) 4.73 (s, 1 H) 4.59 (s, 1 H) 4.06-4.19 (m, 2 H) 3.88 (br d, J =14.95 Hz, 2 H) 3.12-3.29 (m, 4 H) 1.56-1.83 (m, 3 H) 1.28-1.49 (m, 17 H)

(ES, m/z): 388 [M + H]⁺

Example 14—Preparation ofN-hydroxy-4-(5-azaspiro[2.5]octane-1-carbonyl)-2,3,4,5-tetrahydrobenzo[f][1,4]oxazepine-8-carboxamide

Step-1: Methyl4-(5-(tert-butoxycarbonyl)-5-azaspiro[2.5]octane-1-carbonyl)-2,3,4,5-tetrahydrobenzo[f][1,4]oxazepine-8-carboxylate

Into a 1-dram vial, was placed methyl2,3,4,5-tetrahydrobenzo[f][1,4]oxazepine-8-carboxylate (15 mg, 0.072mmol, 1 equiv),5-(tert-butoxycarbonyl)-5-azaspiro[2.5]octane-1-carboxylic acid (27.7mg, 0.109 mmol, 1.5 equiv) and dichloroethane (1 mL). This was followedby the addition of Et₃N (18.3 mg, 0.181 mmol, 2.50 equiv) and DMC (18.36mg, 0.109 mmol, 1.5 equiv) at room temperature. The resulting solutionwas stirred for 2 h at room temperature. The reaction was then quenchedby the addition of water (1 mL). The resulting solution was extractedwith CH₂Cl₂ (2×1 mL). The organic layer was concentrated under vacuum toafford the title compound as a light yellow oil (16 mg, 50% yield) whichwas used without further purification. MS: (ES, m/z): 445 [M+H]⁺.

Step-2:N-Hydroxy-4-(5-azaspiro[2.5]octane-1-carbonyl)-2,3,4,5-tetrahydrobenzo[f][1,4]oxazepine-8-carboxamide

Methyl4-(5-(tert-butoxycarbonyl)-5-azaspiro[2.5]octane-1-carbonyl)-2,3,4,5-tetrahydrobenzo[f][1,4]oxazepine-8-carboxylate(16 mg, 0.036 mmol, 1 equiv) was dissolved in EtOAc (0.5 mL). This wasfollowed by the addition of HCl (4M in Dioxane, 90 μL, 0.36 mmol, 10equiv) at room temperature. The resulting solution was stirred for 4 hat room temperature. The solution was concentrated under vacuum. Theresulting off-white solid was dissolved in MeOH/THF (1:4, 0.5 mL), NH₂OH(50% in water, 24 mg, 0.36 mmol, 10 equiv), and aq. 1N NaOH (0.072 mL, 2equiv). The pH of the reaction was measured to be ˜11. The resultingsolution was stirred overnight at room temperature. The crude productwas purified by Prep-HPLC (Column: XBridge RP C18 OBD, 5 μm, 19×150 mm;Mobile Phase A: Water/0.05% formic acid; Mobile Phase B: MeCN/0.05%formic acid; Flow rate: 23 mL/min; Gradient: 5% B to 35% B in 6.6 min,hold 0.9 min; Detector, UV 254, 220 nm) to afford the title compound asan off-white solid (1.8 mg, 15% yield). MS: (ES, m/z): 346 [M+H]⁺.

TABLE 8 The following compounds were prepared according to the method ofExample 14. Found Structure M + H

(ES, m/z): 332 [M + H]⁺

(ES, m/z): 346 [M + H]⁺

Example 15—Preparation of tert-butyl1-(8-(hydroxycarbamoyl)-2,3,4,5-tetrahydrobenzo[f][1,4]oxazepine-4-carbonyl)-6-azaspiro[2.5]octane-6-carboxylate

Step-1: Methyl4-(6-(tert-butoxycarbonyl)-6-azaspiro[2.5]octane-1-carbonyl)-2,3,4,5-tetrahydrobenzo[f][1,4]oxazepine-8-carboxylate

Into a 1-dram vial, was placed methyl2,3,4,5-tetrahydrobenzo[f][1,4]oxazepine-8-carboxylate (32 mg, 0.072mmol, 1 equiv),5-(tert-butoxycarbonyl)-5-azaspiro[2.5]octane-1-carboxylic acid (22.1mg, 0.086 mmol, 1.2 equiv) and dichloroethane (1 mL). This was followedby the addition of Et₃N (18.2 mg, 0.18 mmol, 2.50 equiv) and DMC (14.6mg, 0.086 mmol, 1.2 equiv) at room temperature. The resulting solutionwas stirred for 2 h at room temperature. The reaction was then quenchedby the addition of water (1 mL). The resulting solution was extractedwith CH₂Cl₂ (2×2 mL). The organic layer was concentrated under vacuum toafford the title compound as a yellow oil (24 mg, 34% yield) which wasused without further purification. MS: (ES, m/z): 445 [M+H]⁺.

Step-2: tert-Butyl1-(8-(hydroxycarbamoyl)-2,3,4,5-tetrahydrobenzo[f][1,4]oxazepine-4-carbonyl)-6-azaspiro[2.5]octane-6-carboxylate

4-(6-(tert-Butoxycarbonyl)-6-azaspiro[2.5]octane-1-carbonyl)-2,3,4,5-tetrahydrobenzo[f][1,4]oxazepine-8-carboxylate(24 mg, 0.053 mmol, 1 equiv) was dissolved in MeOH/THF (1:4, 0.5 mL),NH₂OH (50% in water, 35 mg, 0.53 mmol, 10 equiv), and aq. 1N NaOH (0.106mL, 2 equiv). The resulting solution was stirred overnight at roomtemperature. The crude product was purified by Prep-HPLC (Column:XBridge RP C18 OBD, 5 μm, 19×150 mm; Mobile Phase A: Water/0.05% formicacid; Mobile Phase B: MeCN/0.05% formic acid; Flow rate: 23 mL/min;Gradient: 25% B to 65% B in 6.6 min, hold 0.9 min; Detector, UV 254, 220nm) to afford the title compound as an off-white solid (2.4 mg, 10%yield). MS: (ES, m/z): 446 [M+H]⁺.

Example 16—Preparation of(R)—N-hydroxy-2-methyl-4-(1-methylcyclobutane-1-carbonyl)-2,3,4,5-tetrahydrobenzo[f][1,4]oxazepine-8-carboxamide

Step-1: Methyl (R)-3-bromo-4-(((2-hydroxypropyl)amino)methyl)benzoate

Into a 250-mL round-bottom flask, was placed a solution of methyl3-bromo-4-(bromomethyl)benzoate (7 g, 22.73 mmol, 1 equiv) in MeCN (80mL), potassium carbonate (4.69 g, 33.93 mmol, 1.50 equiv) and(2R)-1-aminopropan-2-ol (1.7 g, 22.63 mmol, 1 equiv). The resultingmixture was stirred for 3 h at room temperature and then concentratedunder vacuum. The residue was diluted with EtOAc (80 mL) and theresulting solution was washed with water (3×30 mL). The organic phasewas concentrated under vacuum to afford the title compound as anoff-white solid (3 g) which was used without further purification. MS:(ES, m/z): 302 [M+H]⁺.

Step-2: Methyl(R)-2-methyl-2,3,4,5-tetrahydrobenzo[f][1,4]oxazepine-8-carboxylate

Into a 100-mL round-bottom flask purged and maintained with an inertatmosphere of nitrogen, was placed a solution of methyl(R)-3-bromo-4-(((2-hydroxypropyl)amino)methyl)benzoate (2.75 g, 9.10mmol, 1 equiv) in isopropanol (32 mL), potassium carbonate (2.53 g,18.31 mmol, 2 equiv) and CuI (520 mg, 2.73 mmol, 0.30 equiv). Theresulting solution was stirred for 21 h at 110° C. in an oil bath. Theresulting mixture was concentrated under vacuum and the residue wasdiluted with EtOAc (100 mL). The resulting mixture was washed with water(3×150 mL) and the organic phase was concentrated, then the residue waspurified by silica gel chromatography (CH₂Cl₂/MeOH, 99:1) to afford thetitle compound as a brown oil (1.1 g, 55% yield). MS: (ES, m/z): 222[M+H]⁺.

Step-3: Methyl(R)-2-methyl-4-(1-methylcyclobutane-1-carbonyl)-2,3,4,5-tetrahydrobenzo[f][1,4]oxazepine-8-carboxylate

Into a 8-mL vial, was placed 1-methylcyclobutane-1-carboxylic acid (52mg, 0.46 mmol, 1 equiv), DMF (4 mL), HATU (205 mg, 0.54 mmol, 1.20equiv), methyl(R)-2-methyl-2,3,4,5-tetrahydrobenzo[f][1,4]oxazepine-8-carboxylate (100mg, 0.45 mmol, 1 equiv) and DIEA (174 mg, 1.35 mmol, 3 equiv). Theresulting mixture was stirred for 16 h at room temperature and thendiluted with water (20 mL). The resulting solution was extracted withEtOAc (2×20 mL). The organic layers combined and concentrated. Theresidue was purified by silica gel chromatography (EtOAc/pet. ether,1:3) to afford the title compound as a yellow oil (88 mg, 61% yield).MS: (ES, m/z): 318 [M+H]⁺.

Step-4:(R)—N-Hydroxy-2-methyl-4-(1-methylcyclobutane-1-carbonyl)-2,3,4,5-tetrahydrobenzo[f][1,4]oxazepine-8-carboxamide

Into a 8-mL vial, were placed methyl(R)-2-methyl-4-(1-methylcyclobutane-1-carbonyl)-2,3,4,5-tetrahydrobenzo[f][1,4]oxazepine-8-carboxylate(88 mg, 0.28 mmol, 1 equiv) and THF/MeOH (4:1, 2 mL). This was followedby addition of NH₂OH (50% in water, 0.55 mL, 30 equiv.) and aq. 1N NaOH(0.55 mL, 2 equiv). The resulting solution was stirred for 3 h at roomtemperature. The crude product was purified by Prep-HPLC (Column XBridgeXP C18 OBD, 5 μm, 19×150 mm; Mobile Phase A: Water/0.05% TFA; MobilePhase B: MeCN/0.05% TFA; Flow rate: 0.7 mL/min; Gradient: 5% B to 40% Bin 7 min; Detector, UV 254 nm) to afford the title compound as anoff-white solid (53 mg, 60% yield). ¹H-NMR (300 MHz, DMSO-d₆) δ (ppm):11.17 (br, 1H), 7.39-7.37 (m, 1H), 7.31 (m, 2H), 4.82-4.60 (m, 1H),4.49-4.21 (m, 2H), 4.11-4.00 (s, 1H), 3.51-3.36 (m, 2H), 2.21 (m, 2H),1.95-1.75 (m, 3H), 1.57-1.54 (m, 1H), 1.33 (m, 6H). MS: (ES, m/z): 319[M+H]⁺.

TABLE 9 The following compound was prepared according to the method ofExample 16, using (2S)-1-aminopropan-2-ol. Found ¹H-NMR (400 MHz,Structure M + H DMSO-d₆) δ(ppm)

(ES, m/z): 319 [M + H]⁺ 11.16 (br, 1H), 7.39-7.37 (m, 1H), 7.31-7.29 (m,2H), 4.82-4-62 (m, 1H), 4.43-4.27 (m, 1H), 4.19-4.08 (m, 1H), 3.80-3.60(m, 1H), 3.45-3.35 (m, 1H), 2.43-2.33 (m, 2H), 1.96- 1.80 (m, 2H),1.79-1.54 (m, 1H), 1.53-1.44 (m, 1H), 1.23 (m, 3H)

Example 17—Preparation of(R)-4-formyl-N-hydroxy-2-methyl-2,3,4,5-tetrahydrobenzo[f][1,4]oxazepine-8-carboxamide

Step-1: Methyl(R)-4-formyl-2-methyl-2,3,4,5-tetrahydrobenzo[f][1,4]oxazepine-8-carboxylate

Into a 8-mL vial, was placed methyl(R)-2-methyl-2,3,4,5-tetrahydro-1,4-benzoxazepine-8-carboxylate (80 mg,0.36 mmol, 1 equiv) and ethyl formate (2 mL, 1 equiv). The resultingsolution was refluxed for 16 h in an oil bath. The resulting mixture wasconcentrated under vacuum to afford the title compound as a yellow oilwhich was used without further purification. MS: (ES, m/z): 250 [M+H]⁺.

Step-2:(R)-4-formyl-N-hydroxy-2-methyl-2,3,4,5-tetrahydrobenzo[f][1,4]oxazepine-8-carboxamide

Into a 8-mL vial, was placed methyl(R)-4-formyl-2-methyl-2,3,4,5-tetrahydrobenzo[f][1,4]oxazepine-8-carboxylate(100 mg, 0.40 mmol, 1 equiv) in THF/MeOH (4:1, 2 mL). To the abovesolution was added aq. 1N NaOH (0.8 mL, 0.80 mmol, 2 equiv) and NH₂OH(50% in water, 0.8 mL, 0.80 mmol, 30 equiv). The resulting solution wasstirred for 3 h at room temperature. The crude product was purified byPrep-HPLC (Column: Waters XBridge XP C18 OBD, 5 μm, 19×150 mm; MobilePhase A: Water/0.05% TFA; Mobile Phase B: MeCN; Flow rate: 0.7 mL/min;Gradient: 5% B to 53% B in 7 min; Detector, UV 254 nm) to afford thetitle compound as a brown solid (7.5 mg, 7% yield). ¹H-NMR (400 MHz,DMSO-d₆) δ(ppm): 11.18 (s, 1H), 9.03 (s, 1H), 8.02 (s, 1H), 7.43-7.32(m, 3H), 4.73-4.67 (m, 1H), 4.32-4.28 (d, J 14.4 Hz, 1H), 4.06-3.81 (m,2H), 3.49-3.40 (m, 1H), 1.28-1.26 (m, 3H). MS: (ES, m/z): 251 [M+H]⁺.

TABLE 10 The following compound was prepared according to the method ofExample 17, using methyl(S)-2-methyl-2,3,4,5-tetrahydro-1,4-benzoxazepine-8-carboxylate. FoundStructure M + H ¹H-NMR (400 MHz, DMSO-d₆) δ (ppm)

(ES, m/z): 251 [M + H]⁺ 11.17 (s, 1H), 9.01 (br, 1H), 7.43-7.32 (m, 3H),4.73-4.71 (m, 1H), 4.32-4.28 (m, 1H), 4.11-3.80 (m, 3H), 3.68 (m, 1H),1.26-1.29 (m, 3H)

Example 18—Preparation of(R)-4-acetyl-N-hydroxy-2-methyl-2,3,4,5-tetrahydrobenzo[f][1,4]oxazepine-8-carboxamide

Step-1: Methyl(R)-4-acetyl-2-methyl-2,3,4,5-tetrahydrobenzo[f][1,4]oxazepine-8-carboxylate

Into a 8-mL vial, was placed a solution of methyl(R)-2-methyl-2,3,4,5-tetrahydro-1,4-benzoxazepine-8-carboxylate (80 mg,0.36 mmol, 1 equiv) in CH₂Cl₂ (2 mL) and triethylamine (110 mg, 1.09mmol, 3 equiv). This was followed by the addition of a solution ofacetyl chloride (31 mg, 0.39 mmol, 1.10 equiv) in CH₂Cl₂ (0.5 mL)dropwise with stirring at 0° C. The resulting solution was stirred for18 h at room temperature. The reaction mixture was concentrated undervacuum to afford the title compound as a green oil which was usedwithout further purification. MS: (ES, m/z): 264 [M+H]⁺.

Step-2:(R)-4-Acetyl-N-hydroxy-2-methyl-2,3,4,5-tetrahydrobenzo[f][1,4]oxazepine-8-carboxamide

Into a 8-mL vial, was placed a solution of methyl(R)-4-acetyl-2-methyl-2,3,4,5-tetrahydrobenzo[f][1,4]oxazepine-8-carboxylate(90 mg, 0.34 mmol, 1 equiv) in THF/MeOH (4:1, 2 mL). aq. 1N NaOH (0.68mL, 2 equiv) and NH₂OH (50% in water, 0.67 mL, 30 equiv) were added. Theresulting solution was stirred for 14 h at room temperature. The crudeproduct was purified by Prep-HPLC (Column: Sunfire Prep C18 OBD, 5 μm,19×150 mm; Mobile Phase A: Water/0.05% TFA; Mobile Phase B: MeCN; Flowrate: 25 mL/min; Gradient: 4% B to 18% B in 6 min; Detector, UV 254, 220nm) to afford the title compound as a green oil (12.5 mg, 10% yield).¹H-NMR (400 MHz, DMSO-d₆) δ(ppm): 11.18-11.16 (br, 1H), 9.03 (s, 1H),7.42-7.25 (m, 3H), 4.76-4.68 (m, 1H), 4.53-4.49 (d, J=8.2 Hz, 1H),4.12-3.86 (m, 2H), 3.42-3.41 (m, 1H), 2.01-1.98 (d, J=12.8 Hz, 3H),1.31-1.25 (m, 3H). MS: (ES, m/z): 265 [M+H]⁺.

TABLE 11 The following compound was prepared according to the method ofExample 18, using methyl(S)-2-methyl-2,3,4,5-tetrahydro-1,4-benzoxazepine-8-carboxylate. FoundStructure M + H ¹H-NMR (400 MHz, DMSO-d₆) δ (ppm)

(ES, m/z): 265 [M + H]⁺ 11.17-11.15 (br, 1H), 9.03 (s, 1H), 7.44- 7.28(m, 3H), 4.77-4.72 (m, 1H), 4.68- 4.34 (m, 1H), 4.15-3.98 (m, 2H), 3.67-3.39 (m, 1H), 2.07-1.98 (d, J = 12.8 Hz, 3H), 1.31-1.26 (m, 3H)

Example 19—Preparation of(R)—N-hydroxy-2-isopropyl-4-(tetrahydro-2H-pyran-4-carbonyl)-2,3,4,5-tetrahydrobenzo[f][1,4]oxazepine-8-carboxamide

Step-1: Methyl(R)-3-bromo-4-(((2-hydroxy-3-methylbutyl)amino)methyl)benzoate

Into a 500-mL round-bottom flask, was placed(R)-1-amino-3-methylbutan-2-ol (6.41 g, 62.13 mmol, 2 equiv), MeCN (100mL) and K₂CO₃ (6.44 g, 46.60 mmol, 1.5 equiv). This was followed by theaddition of methyl 3-bromo-4-(bromomethyl)benzoate (9.52 g, 30.91 mmol,1 equiv) in several batches. The resulting solution was stirred for 16 hat room temperature. The resulting mixture was concentrated undervacuum. The residue was dissolved in EtOAc (200 mL) and washed with H₂O(2×100 mL). The organic layer was dried over anhydrous Na₂SO₄, filtered,and concentrated. The residue was purified by silica gel chromatography(EtOAc/pet. ether, 3:2) to afford the title compound as a yellow solid(6.48 g, 63% yield). MS: (ES, m/z): 330 [M+H]⁺.

Step-2: Methyl(R)-2-isopropyl-2,3,4,5-tetrahydrobenzo[f][1,4]oxazepine-8-carboxylate

Into a 100-mL pressure tank reactor purged and maintained with an inertatmosphere of nitrogen, was placed methyl(R)-3-bromo-4-(((2-hydroxy-3-methylbutyl)amino)methyl)benzoate (4.91 g,14.87 mmol, 1 equiv), isopropanol (50 mL), K₂CO₃ (3.09 g, 22.36 mmol,1.5 equiv) and CuI (1.42 g, 7.46 mmol, 0.5 equiv). The resultingsolution was stirred for 16 h at 110° C. in an oil bath. The resultingmixture was concentrated under vacuum. The residue was dissolved inCH₂Cl₂ (200 mL) and washed with H₂O (3×100 mL). The organic layer wasdried over anhydrous MgSO₄, filtered, and concentrated. The residue waspurified by C18 chromatography (MeCN/H₂O+0.05% TFA, 1:3) to afford theTFA salt of the title compound as a green solid (1.5 g, 40% yield). MS:(ES, m/z): 250 [M+H]⁺.

Step-3: Methyl(R)-2-isopropyl-4-(tetrahydro-2H-pyran-4-carbonyl)-2,3,4,5-tetrahydrobenzo[f][1,4]oxazepine-8-carboxylate

Into a 8-mL vial, were placed methyl(R)-2-isopropyl-2,3,4,5-tetrahydrobenzo[f][1,4]oxazepine-8-carboxylate·TFA(100 mg, 0.40 mmol, 1 equiv) and DMF (10 mL). This was followed by theaddition of tetrahydro-2H-pyran-4-carboxylic acid (62.4 mg, 0.48 mmol,1.2 equiv), HATU (183 mg, 0.76 mmol, 1.2 equiv) and DIEA (155 mg, 1.20mmol, 3 equiv) at 0° C. The resulting mixture was stirred for 16 h atroom temperature and then diluted with EtOAc (50 mL). The resultingmixture was washed with H₂O (5×50 mL). The organic layer was dried overanhydrous Na₂SO₄, filtered, and concentrated to afford the titlecompound as yellow oil (150 mg) which was used without furtherpurification. MS: (ES, m/z): 362 [M+H]⁺.

Step-4:(R)—N-hydroxy-2-isopropyl-4-(tetrahydro-2H-pyran-4-carbonyl)-2,3,4,5-tetrahydrobenzo[f][1,4]oxazepine-8-carboxamide

Into a 8-mL vial, was placed methyl(R)-2-isopropyl-4-(tetrahydro-2H-pyran-4-carbonyl)-2,3,4,5-tetrahydrobenzo[f][1,4]oxazepine-8-carboxylate(150 mg, 0.42 mmol, 1 equiv) and THF/MeOH (4:1, 1.5 mL). Then NH₂OH (50%in water, 0.84 mL, 12.73 mmol, 30 equiv) and aq. 1N NaOH (0.84 mL, 0.82mmol, 2 equiv) were added at the same time. The resulting solution wasstirred for 16 h at room temperature. The crude product was purified byPrep-HPLC (Column: Sunfire Prep C18 OBD, 5 μm, 19×150 mm; Mobile PhaseA: Water/0.05% formic acid; Mobile Phase B: MeCN; Flow rate: 25 mL/min;Gradient: 10% B to 30% B in 8 min; Detector, UV 254, 220 nm) to affordthe title compound as a yellow solid (21.6 mg, 13% yield). ¹H-NMR (400MHz, DMSO-d₆) δ(ppm): 11.20 (br, 1H), 7.52-7.50 (d, J=8.0 Hz, 1H),7.44-7.42 (d, J=8.8 Hz, 1H), 7.39-7.36 (m, 1H), 7.31-7.27 (m, 1H),4.92-4.88 (d, J=16.4 Hz, 0.5H), 4.80-4.76 (d, J=14.8 Hz, 0.4H),4.61-4.57 (d, J=16.0 Hz, 0.5H), 4.40-4.36 (d, J=15.2 Hz, 0.4H),4.15-4.12 (d, J=11.6 Hz, 0.5H), 3.99-3.96 (d, J=11.6 Hz, 0.5H),3.80-3.78 (m, 2H), 3.70-3.68 (m, 1H), 3.54-3.48 (m, 1H), 3.41-3.32 (m,2H), 2.98 (m, 0.5H), 2.88-2.86 (m, 0.4H), 1.98-1.86 (m, 1H), 1.57-1.48(m, 2H), 1.41-1.33 (m, 1H), 1.22-1.19 (d, J=13.6 Hz, 1H), 1.08-1.02 (m,6H). MS: (ES, m/z): 363 [M+H]⁺.

TABLE 12 The following compound was prepared according to the method ofExample 19. Found Structure M + H ¹H-NMR (400 MHz, DMSO-d₆) δ (ppm)

(ES, m/z): 347 [M + H]⁺ 11.19 (br, 1H), 7.39-7.28 (m, 3H), 4.78-4.64 (m,1H), 4.44-4.36 (t, 1H), 3.90-3.64 (m, 2H), 3.53-3.47 (m, 1H), 2.39-2.32(m, 2H), 1.94-1.89 (m, 2H), 1.88-1.75 (m, 1H), 1.59-1.56 (m, 1H), 1.34(s, 3H), 1.08-1.03 (m, 6H)

Example 20—Preparation of(R)-4-formyl-N-hydroxy-2-isopropyl-2,3,4,5-tetrahydrobenzo[f][1,4]oxazepine-8-carboxamide

Step-1: Methyl(R)-4-formyl-2-isopropyl-2,3,4,5-tetrahydrobenzo[f][1,4]oxazepine-8-carboxylate

Into a 8-mL vial, was placed methyl(R)-2-isopropyl-2,3,4,5-tetrahydrobenzo[f][1,4]oxazepine-8-carboxylate·TFA(80 mg, 0.32 mmol, 1 equiv) and ethyl formate (1.5 mL). The resultingsolution was stirred for 16 h at 60° C. in an oil bath. The resultingmixture was concentrated under vacuum to afford the title compound asyellow oil (90 mg) which was used without further purification. MS: (ES,m/z): 278 [M+H]⁺.

Step-2:(R)-4-Formyl-N-hydroxy-2-isopropyl-2,3,4,5-tetrahydrobenzo[f][1,4]oxazepine-8-carboxamide

Into a 8-mL vial, was placed methyl(R)-4-formyl-2-isopropyl-2,3,4,5-tetrahydrobenzo[f][1,4]oxazepine-8-carboxylate(89 mg, 0.32 mmol, 1 equiv) in THF/MeOH (4:1, 1.5 mL). Then NH₂OH (50%in water, 0.64 mL, 9.70 mmol, 30 equiv) and aq. 1N NaOH (0.64 mL, 0.65mmol, 2 equiv) were added at the same time. The resulting solution wasstirred for 2 h at room temperature. The crude product was purified byPrep-HPLC (Column: Sunfire Prep C18 OBD, 5 μm, 19×150 mm; Mobile PhaseA: Water/0.05% formic acid; Mobile Phase B: MeCN; Flow rate: 25 mL/min;Gradient: 5% B to 36% B in 7 min; Detector, UV 254, 220 nm) to affordthe title compound as a white solid (11.3 mg, 11% yield). ¹H-NMR (400MHz, DMSO-d₆) δ(ppm): 11.20 (br, 1H), 8.20 (s, 4H), 8.06 (s, 0.6H),7.45-7.32 (m, 3H), 4.81-4.72 (m, 1H), 4.54-4.50 (d, J=16.0 Hz, 0.4H),4.30-4.27 (d, J=14.8 Hz, 0.6H), 4.09-4.05 (d, J=13.2 Hz, 0.4H),3.90-3.83 (m, 0.6H), 3.61-3.49 (m, 1.5H), 3.43-3.37 (m, 0.5H), 1.95-1.88(m, 1H), 1.09-1.03 (m, 6H). MS: (ES, m/z): 279 [M+H]⁺.

Example 21—Preparation of(R)—N-hydroxy-2-(methoxymethyl)-4-(tetrahydro-2H-pyran-4-carbonyl)-2,3,4,5-tetrahydrobenzo[f][1,4]oxazepine-8-carboxamide

Step-1: Methyl(R)-3-bromo-4-(((2-hydroxy-3-methoxypropyl)amino)methyl)benzoate

Into a 500-mL round-bottom flask, was placed a solution of(R)-1-amino-3-methoxypropan-2-ol (5.7 g, 54.22 mmol, 1.1 equiv) in MeCN(150 mL) and K₂CO₃ (10 g, 72.46 mmol, 1.5 equiv). This was followed bythe addition of a solution of methyl 3-bromo-4-(bromomethyl)benzoate(15.2 g, 49.36 mmol, 1 equiv) in MeCN (100 mL) dropwise with stirring atroom temperature. The resulting mixture was stirred for 16 h at roomtemperature. The resulting mixture was concentrated under vacuum. Theresidue was diluted with H₂O (100 mL) and extracted with EtOAc (3×100mL). The organic layer was washed with H₂O (2×100 mL) and concentratedunder vacuum. The residue was purified by silica gel chromatography(EtOAc/pet. ether, 1:4) to afford the title compound as a yellow solid(6.4 g, 39% yield). MS: (ES, m/z): 332 [M+H]⁺.

Step-2: Methyl(R)-2-(methoxymethyl)-2,3,4,5-tetrahydrobenzo[f][1,4]oxazepine-8-carboxylate

Into a 150-mL pressure tank reactor purged and maintained with an inertatmosphere of nitrogen, was placed a solution of methyl(R)-3-bromo-4-(((2-hydroxy-3-methoxypropyl)amino)methyl)benzoate (6.4 g,19.27 mmol, 1 equiv) in isopropanol (130 mL), K₂CO₃ (4.01 g, 29.06 mmol,1.5 equiv) and CuI (1.47 g, 7.74 mmol, 0.4 equiv). The resultingsolution was stirred for 16 h at 110° C. in an oil bath. The resultingmixture was concentrated under vacuum. The residue was diluted with H₂O(100 mL) and extracted with CH₂Cl₂ (3×100 mL). The organic layer waswashed with H₂O (2×100 mL) and concentrated under vacuum. The residuewas purified by C18 chromatography (MeCN/H₂O+0.05% TFA, 88:12) to affordthe TFA salt of the title compound as a yellow solid (3.5 g, 50% yield).MS: (ES, m/z): 252 [M+H]⁺.

Step-3: Methyl(R)-2-(methoxymethyl)-4-(tetrahydro-2H-pyran-4-carbonyl)-2,3,4,5-tetrahydrobenzo[f][1,4]oxazepine-8-carboxylate

Into a 8-mL vial, was placed a solution of methyl(R)-2-(methoxymethyl)-2,3,4,5-tetrahydrobenzo[f][1,4]oxazepine-8-carboxylate·TFA(100 mg, 0.27 mmol, 1 equiv) in DMF (2 mL) and HATU (125 mg, 0.33 mmol,1.20 equiv). This was followed by the addition of a solution oftetrahydro-2H-pyran-4-carboxylic acid (43 mg, 0.33 mmol, 1.2 equiv) inDMF (0.5 mL) dropwise with stirring at 0° C. To this was added DIEA (106mg, 0.82 mmol, 3 equiv) at 0° C. The resulting mixture was stirred for18 h at room temperature and then diluted with H₂O (10 mL). Theresulting solution was extracted with EtOAc (3×20 mL). The organic layerwas washed with H₂O (2×20 mL) and brine (20 mL), then dried overanhydrous Na₂SO₄, filtered, and concentrated under vacuum. The residuewas purified by silica gel chromatography (EtOAc/pet. ether, 2:1) toafford the title compound as a colorless oil (94 mg, 94% yield). MS:(ES, m/z): 364 [M+H]⁺.

Step-4:(R)—N-Hydroxy-2-(methoxymethyl)-4-(tetrahydro-2H-pyran-4-carbonyl)-2,3,4,5-tetrahydrobenzo[f][1,4]oxazepine-8-carboxamide

Into a 8-mL vial, was placed a solution of methyl(R)-2-(methoxymethyl)-4-(tetrahydro-2H-pyran-4-carbonyl)-2,3,4,5-tetrahydrobenzo[f][1,4]oxazepine-8-carboxylate(94 mg, 0.26 mmol, 1 equiv) in THF/MeOH (4:1, 3 mL). Then aq. 1N NaOH(0.52 mL, 2.00 equiv) and NH₂OH (50% in H₂O, 0.51 mL, 30 equiv) wereadded simultaneously. The resulting solution was stirred for 3 h at roomtemperature. The crude product was purified by Prep-HPLC (Column:XBridge RP C18 OBD, 5 μm, 19×150 mm; Mobile Phase A: Water/0.05% formicacid; Mobile Phase B: MeCN; Flow rate: 23 mL/min; Gradient: 5% B to 30%B in 7 min; Detector, UV 254 nm) to afford the title compound as a whitesolid (27.7 mg, 29% yield). ¹H-NMR (400 MHz, DMSO-d₆) δ(ppm): 11.15 (br,1H), 9.08 (br, 1H), 7.53-7.29 (m, 3H), 4.91-4.43 (m, 2H), 4.18-4.01 (m,1H), 3.98-3.93 (m, 1H), 3.80-3.49 (m, 5H), 3.40-3.32 (m, 5H), 2.98-2.85(m, 1H), 1.57-1.41 (m, 3H), 1.30-1.27 (m, 1H). MS: (ES, m/z): 365[M+H]⁺.

TABLE 13 The following compounds were prepared according to the methodof Example 21, using (S)-1-amino-3-methoxypropan-2-ol where appropriate.Found Structure M + H ¹H-NMR (400 MHz, DMSO-d₆) δ (ppm)

(ES, (m/z): 349 [M + H]⁺ 11.18 (br, 1H), 9.02 (br, 1H), 7.40-7.30 (m,3H), 4.81- 4.68 (m, 1H), 4.38-4.13 (m, 2H), 3.76-3.47 (m, 4H), 3.35-3.32 (d, J = 12.0 Hz, 3H), 2.35-2.33 (m, 2H), 1.94-1.75 (m, 3H),1.58-1.55 (m, 1H), 1.33 (s, 3H)

(ES, (m/z): 365 [M + H]⁺ 11.18 (br, 1H), 9.03 (br, 1H), 7.53-7.29 (m,3H), 4.91- 4.43 (m, 2H), 4.19-4.09 (m, 1H), 4.01-3.96 (m, 1H), 3.93-3.51 (m, 5H), 3.41-3.32 (m, 5H), 2.99-2.87 (m, 1H), 1.54- 1.45 (m, 3H),1.30-1.27 (d, J = 12.8 Hz, 1H)

(ES, (m/z): 349 [M + H]⁺ 11.18 (br, 1H), 9.03 (br, 1H), 7.40-7.30 (m,3H), 4.81- 4.68 (m, 1H), 4.44-4.13 (m, 2H), 3.76-3.48 (m, 4H), 3.35-3.33(d, J = 8.0 Hz, 3H), 2.35-2.33 (m, 2H), 1.94-1.75 (m, 3H), 1.58-1.55 (m,1H), 1.33 (s, 3H)

Example 22—Preparation of(R)-4-formyl-N-hydroxy-2-(methoxymethyl)-2,3,4,5-tetrahydrobenzo[f][1,4]oxazepine-8-carboxamide

Step-1: Methyl(R)-4-formyl-2-(methoxymethyl)-2,3,4,5-tetrahydrobenzo[f][1,4]oxazepine-8-carboxylate

Methyl(R)-2-(methoxymethyl)-2,3,4,5-tetrahydrobenzo[f][1,4]oxazepine-8-carboxylate·TFA(100 mg, 0.27 mmol, 1 equiv) was dissolved in CH₂Cl₂ (2 mL) and Et₃N (28mg, 0.27 mmol, 1 equiv) was added. The resulting mixture wasconcentrated under vacuum. The residue and ethyl formate (2.5 mL) wereadded to a 10 mL sealed tube. The resulting solution was stirred for 18h at 60° C. in an oil bath. The mixture was concentrated under vacuum toafford the title compound as light yellow oil (70 mg), which was usedwithout further purification. MS: (ES, m/z): 280 [M+H]⁺.

Step-2:(R)-4-Formyl-N-hydroxy-2-(methoxymethyl)-2,3,4,5-tetrahydrobenzo[f][1,4]oxazepine-8-carboxamide

Into a 8-mL vial, was placed a solution of methyl(R)-4-formyl-2-(methoxymethyl)-2,3,4,5-tetrahydrobenzo[f][1,4]oxazepine-8-carboxylate(70 mg, 0.25 mmol, 1 equiv) in THF/MeOH (4:1, 2 mL). Then aq. 1N NaOH(0.50 mL, 2 equiv) and NH₂OH (50% in H₂O, 0.50 mL, 30 equiv) were addedsimultaneously. The resulting solution was stirred for 3 h at roomtemperature. The crude product was purified by Prep-HPLC (Column:XBridge RP C18 OBD, 5 μm, 19×150 mm; Mobile Phase A: Water/0.05% formicacid; Mobile Phase B: MeCN; Flow rate: 20 mL/min; Gradient: 5% B to 15%B in 7 min; Detector, UV 254, 220 nm) to afford the title compound as abrown solid (7.5 mg, 11% yield). ¹H-NMR (400 MHz, DMSO-d₆) δ(ppm): 11.13(br, 1H), 9.05-9.04 (br, 1H), 8.20-8.04 (d, 1H), 7.45-7.33 (m, 3H),4.78-4.73 (m, 1H), 4.55-4.31 (m, 1H), 4.09-3.83 (m, 2H), 3.61-3.43 (m,3H), 3.34-3.33 (d, 3H). MS: (ES, m/z): 281 [M+H]⁺.

TABLE 14 The following compounds were prepared according to the methodof Example 22, using methyl(S)-2-(methoxymethyl)-2,3,4,5-tetrahydrobenzo[f][1,4]oxazepine-8-carboxylate•TFA. Found Structure M + H ¹H-NMR (400 MHz, DMSO-d₆) δ (ppm)

(ES, m/z): 281 [M + H]⁺ 11.18 (br, 1H), 9.08 (br, 1H), 8.21-8.04 (d,1H), 7.45-7.34 (m, 3H), 4.78-4.73 (m, 1H), 4.56-4.32 (m, 1H), 4.09-3.84(m, 2H), 3.62-3.44 (m, 3H), 3.34-3.33 (d, J = 3.60 Hz, 3H)

Example 23—Preparation of(R)—N-hydroxy-2-phenyl-4-(tetrahydro-2H-pyran-4-carbonyl)-2,3,4,5-tetrahydrobenzo[f][1,4]oxazepine-8-carboxamide

Step-1: Methyl(R)-3-bromo-4-(((2-hydroxy-2-phenylethyl)amino)methyl)benzoate

Into a 500-mL round-bottom flask, was placed a solution of(R)-2-amino-1-phenylethan-1-ol (10 g, 72.90 mmol, 1.5 equiv) in MeCN(100 mL), then K₂CO₃ (8.7 g, 62.49 mmol, 1.3 equiv) was added. This wasfollowed by the slow addition of a solution of methyl3-bromo-4-(bromomethyl)benzoate (15 g, 48.71 mmol, 1 equiv) in MeCN (120mL). The resulting mixture was stirred overnight at room temperature andthen concentrated under vacuum. The residue was dissolved in EtOAc (350mL) and washed with H₂O (3×100 mL). The organic layer was concentratedunder vacuum and purified by silica gel chromatography (EtOAc/pet.ether, 1:3) to afford the title compound as a yellow solid (9.7 g, 57%yield). MS: (ES, m/z): 364 [M+H]⁺.

Step-2: Methyl(R)-2-phenyl-2,3,4,5-tetrahydrobenzo[f][1,4]oxazepine-8-carboxylate

Into a 100-mL sealed tube, was placed a solution of methyl(R)-3-bromo-4-(((2-hydroxy-2-phenylethyl)amino)methyl)benzoate (4.0 g,10.98 mmol, 1 equiv) in isopropanol (80 mL), then K₂CO₃ (3.1 g, 22.43mmol, 2 equiv) was added. This was followed by the addition of CuI (630mg, 3.31 mmol, 0.3 equiv). The resulting mixture was stirred overnightat 110° C. in an oil bath. The solids were filtered out and the filtratewas concentrated under vacuum. The residue was dissolved in EtOAc (300mL) and washed with H₂O (3×150 mL). The organic layer was concentratedunder vacuum. The residue was dissolved in DMF and purified by C18chromatography (MeCN/H₂O+0.05% TFA, 5% to 20% in 15 min) to afford theTFA salt of the title compound as a white solid (1.9 g, 61% yield). MS:(ES, m/z): 284 [M+H]⁺.

Step-3: Methyl(R)-2-phenyl-4-(tetrahydro-2H-pyran-4-carbonyl)-2,3,4,5-tetrahydrobenzo[f][1,4]oxazepine-8-carboxylate

Into a 8-mL vial, was placed a solution of methyl(R)-2-phenyl-2,3,4,5-tetrahydrobenzo[f][1,4]oxazepine-8-carboxylate·TFA(100 mg, 0.77 mmol, 1 equiv) in DMF (2.0 mL), then HATU (114.8 mg, 0.30mmol, 1.2 equiv) and tetrahydro-2H-pyran-4-carboxylic acid (39.3 mg,0.10 mmol, 1.2 equiv) were added. To this was added DIEA (97.2 mg, 0.75mmol, 3 equiv) at 0° C. The resulting mixture was stirred overnight atroom temperature. The reaction was diluted with EtOAc (20 mL) and washedwith H₂O (3×15 mL). The organic layer was concentrated under vacuum. Theresidue was purified by silica gel chromatography (EtOAc/pet. ether,3:2) to afford the title compound as a colorless oil (90 mg, 30% yield).MS: (ES, m/z): 396 [M+H]⁺.

Step-4:(R)—N-Hydroxy-2-phenyl-4-(tetrahydro-2H-pyran-4-carbonyl)-2,3,4,5-tetrahydrobenzo[f][1,4]oxazepine-8-carboxamide

Into a 8-mL vial, was placed a solution of methyl(R)-2-phenyl-4-(tetrahydro-2H-pyran-4-carbonyl)-2,3,4,5-tetrahydrobenzo[f][1,4]oxazepine-8-carboxylate(90 mg, 0.23 mmol, 1 equiv) in THF/MeOH (4:1, 2 mL), then aq. 1N NaOH(0.48 mL, 2 equiv) and NH₂OH (50% in H₂O, 0.48 mL, 30 equiv) were addedsimultaneously. The resulting solution was stirred for 2 h at roomtemperature. The crude product was purified by Prep-HPLC (Column:XBridge RP C18 OBD, 5 μm, 19×150 mm; Mobile Phase A: Water/0.1% formicacid; Mobile Phase B: MeCN; Flow rate: 25 mL/min; Gradient: 30% B to 70%B in 7 min; Detector, UV 254, 220 nm) to afford the title compound as awhite solid (60.9 mg, 67% yield). ¹H-NMR (400 MHz, DMSO-d₆) δ(ppm):11.16 (s, 1H), 9.02 (s, 1H), 7.61-7.35 (m, 8H), 5.15-5.03 (m, 1H),4.95-4.90 (m, 1H), 4.74-4.48 (m, 1H), 4.29-4.08 (m, 1H), 3.94-3.66 (m,3H), 3.45-3.32 (m, 2H), 3.27-2.87 (m, 1H), 1.54-1.49 (m, 4H). MS: (ES,m/z): 397 [M+H]⁺.

TABLE 15 The following compounds were prepared according to the methodof Example 23. Found ¹H-NMR (400 MHz, Structure M + H DMSO-d₆ ) δ (ppm)

(ES, m/z): 381 [M + H]⁺ 11.15 (s, 1H), 9.02 (s, 1H), 7.51- 7.35 (m, 8H),5.11 (m, 1H), 4.98- 4.94 (m, 1H), 4.45-3.72 (m, 2H), 2.50 (s, 2H),1.91-1.57 (m, 4H), 1.35 (m, 3H)

Example 24—Preparation of(R)-4-formyl-N-hydroxy-2-phenyl-2,3,4,5-tetrahydrobenzo[f][1,4]oxazepine-8-carboxamide

Step-1: Methyl(R)-4-formyl-2-phenyl-2,3,4,5-tetrahydrobenzo[f][1,4]oxazepine-8-carboxylate

Into a 8-mL vial, was placed a solution of methyl(R)-2-phenyl-2,3,4,5-tetrahydrobenzo[f][1,4]oxazepine-8-carboxylate·TFA(110 mg, 1.48 mmol, 1 equiv) in CH₂Cl₂ (2.0 mL). This was followed bythe addition of Et₃N (27.6 mg, 1 equiv). The resulting mixture wasconcentrated under vacuum. Then ethyl formate (3.0 mL) was added. Theresulting solution was stirred overnight at room temperature. Theresulting mixture was concentrated under vacuum. The residue waspurified by silica gel chromatography (EtOAc/pet. ether, 3:1) to affordthe title compound as a yellow oil (140 mg, 30% yield). MS: (ES, m/z):312 [M+H]⁺.

Step-2:(R)-4-Formyl-N-hydroxy-2-phenyl-2,3,4,5-tetrahydrobenzo[f][1,4]oxazepine-8-carboxamide

Into a 8-mL vial, was placed a solution of methyl(R)-4-formyl-2-phenyl-2,3,4,5-tetrahydrobenzo[f][1,4]oxazepine-8-carboxylate(140 mg, 0.45 mmol, 1 equiv) in THF/MeOH (4:1, 2.5 mL), then aq. 1N NaOH(0.88 mL, 2 equiv) and NH₂OH (50% in H₂O, 0.88 mL, 30 equiv) were addedsimultaneously. The resulting solution was stirred for 2 h at roomtemperature. The crude product was purified by Prep-HPLC (Column:XBridge RP C18 OBD, 5 μm, 19×150 mm; Mobile Phase A: Water/0.1% formicacid; Mobile Phase B: MeCN; Flow rate: 25 mL/min; Gradient: 30% B to 70%B in 7 min; Detector, UV 254, 220 nm) to afford the title compound as awhite solid (60.9 mg, 67% yield). ¹H-NMR (400 MHz, DMSO-d₆) δ(ppm):11.14 (br, 1H), 9.03 (s, 1H), 8.27-8.15 (m, 1H), 7.57-7.38 (m, 8H),4.99-4.86 (m, 2H), 4.66-4.37 (m, 1H), 4.33-4.02 (m, 1H), 3.81-3.57 (m,1H). MS: (ES, m/z): 313 [M+H]⁺.

Example 25—Preparation of(S)—N-hydroxy-2-phenyl-4-(tetrahydro-2H-pyran-4-carbonyl)-2,3,4,5-tetrahydrobenzo[f][1,4]oxazepine-8-carboxamide

Step-1: Methyl(S)-3-bromo-4-(((2-hydroxy-2-phenylethyl)amino)methyl)benzoate

Into a 500-mL round-bottom flask, was placed a solution of(S)-2-amino-1-phenylethan-1-ol (10 g, 72.90 mmol, 1.5 equiv) in MeCN(150 mL), then K₂CO₃ (8.7 g, 62.49 mmol, 1.3 equiv) was added. This wasfollowed by the slow addition of a solution of methyl3-bromo-4-(bromomethyl)benzoate (15 g, 48.71 mmol, 1 equiv) in MeCN (100mL). The resulting mixture was stirred overnight at room temperature andthen concentrated under vacuum. The solution was diluted with H₂O (200mL) and extracted with EtOAc (3×200 mL). The organic layer was washedwith H₂O (2×200 mL) and concentrated under vacuum. The residue waspurified by silica gel chromatography (EtOAc/pet. ether, 1:2) to affordthe title compound as a white solid (7.9 g, 45% yield). MS: (ES, m/z):364 [M+H]⁺.

Step-2: Methyl(S)-2-phenyl-2,3,4,5-tetrahydrobenzo[f][1,4]oxazepine-8-carboxylate

Into a 100-mL sealed tube, was placed a solution of methyl(S)-3-bromo-4-(((2-hydroxy-2-phenylethyl)amino)methyl)benzoate (7.9 g,21.69 mmol, 1 equiv) in isopropanol (180 mL), then K₂CO₃ (4.49 g, 32.54mmol, 1.5 equiv) was added. This was followed by the addition of CuI(1.24 g, 6.53 mmol, 0.3 equiv). The resulting mixture was stirredovernight at 110° C. in an oil bath. The reaction was concentrated undervacuum and diluted with H₂O (150 mL) and extracted with CH₂Cl₂ (3×100mL). The organic layer was concentrated under vacuum. The residue waspurified by silica gel chromatography (EtOAc/pet. ether, 1:1) to affordthe title compound as a brown oil (2.9 g, 47% yield). MS: (ES, m/z): 284[M+H]⁺.

Step-3: Methyl(S)-2-phenyl-4-(tetrahydro-2H-pyran-4-carbonyl)-2,3,4,5-tetrahydrobenzo[f][1,4]oxazepine-8-carboxylate

Into a 8-mL vial, a solution of methyl(S)-2-phenyl-2,3,4,5-tetrahydrobenzo[f][1,4]oxazepine-8-carboxylate (100mg, 0.35 mmol, 1 equiv) in DMF (2.0 mL), HATU (161 mg, 0.42 mmol, 1.2equiv) and tetrahydro-2H-pyran-4-carboxylic acid (46 mg, 0.35 mmol, 1equiv), and DIEA (136 mg, 1.05 mmol, 3 equiv) was stirred overnight atroom temperature. The reaction was diluted with H₂O (10 mL) andextracted with EtOAc (3×10 mL). The organic layer was washed with H₂O(3×10 mL) and concentrated under vacuum. The residue was purified bysilica gel chromatography (EtOAc/pet. ether, 1:3) to afford the titlecompound as a yellow oil (100 mg, 72% yield). MS: (ES, m/z): 396 [M+H]⁺.

Step-4:(S)—N-Hydroxy-2-phenyl-4-(tetrahydro-2H-pyran-4-carbonyl)-2,3,4,5-tetrahydrobenzo[f][1,4]oxazepine-8-carboxamide

Into a 8-mL vial, was placed a solution of methyl(S)-2-phenyl-4-(tetrahydro-2H-pyran-4-carbonyl)-2,3,4,5-tetrahydrobenzo[f][1,4]oxazepine-8-carboxylate(100 mg, 0.25 mmol, 1 equiv) in THF/MeOH (4:1, 2 mL), then aq. 1N NaOH(0.42 mL, 2 equiv) and NH₂OH (50% in H₂O, 0.42 mL, 30 equiv) were addedsimultaneously. The resulting solution was stirred for 2 h at roomtemperature. The crude product was purified by Prep-HPLC (Column:XBridge RP C18 OBD, 5 μm, 19×150 mm; Mobile Phase A: Water/0.05% formicacid; Mobile Phase B: MeCN; Flow rate: 20 mL/min; Gradient: 30% B to 70%B in 10 min; Detector, UV 254 nm) to afford the title compound as awhite solid (54.3 mg, 54% yield). ¹H-NMR (400 MHz, DMSO-d₆) δ(ppm):11.16 (s, 1H), 9.03 (s, 1H), 7.61-7.52 (m, 2H), 7.51-7.32 (m, 6H),5.15-5.03 (m, 1H), 4.95-4.86 (m, 1H), 4.81-4.46 (m, 1H), 4.33-4.06 (m,1H), 3.98-3.89 (m, 0.5H), 3.88-3.77 (m, 2H), 3.76-3.66 (m, 0.5H),3.48-3.35 (m, 2H), 3.13-2.98 (m, 0.5H), 2.97-2.84 (m, 0.5H), 1.65-1.37(m, 3H), 1.31-1.20 (m, 1H). MS: (ES, m/z): 397 [M+H]⁺.

TABLE 16 The following compounds were prepared according to the methodof Example 25. Found Structure M + H ¹H-NMR (400 MHz, DMSO-d₆) δ (ppm)

(ES, m/z): 381 [M + H]⁺ 11.16 (s, 1H), 9.02 (s, 1H), 7.51-7.35 (m, 8H),5.26-5.08 (m, 1H), 5.03-4.79 (m, 1H), 4.56-4.41 (m, 1H), 4.11-3.62 (m,2H), 2.49-2.18 (m, 2H), 1.98-1.53 (m, 4H), 1.41-1.28 (s, 3H)

Example 26—Preparation of(S)-4-formyl-N-hydroxy-2-phenyl-2,3,4,5-tetrahydrobenzo[f][1,4]oxazepine-8-carboxamide

Step-1: Methyl(S)-4-formyl-2-phenyl-2,3,4,5-tetrahydrobenzo[f][1,4]oxazepine-8-carboxylate

Into a 8-mL vial, was placed methyl(S)-2-phenyl-2,3,4,5-tetrahydrobenzo[f][1,4]oxazepine-8-carboxylate (100mg, 0.35 mmol, 1 equiv) and ethyl formate (3 mL). The resulting solutionwas stirred overnight at 61° C. in an oil bath. The resulting mixturewas concentrated under vacuum. The residue was purified by silica gelchromatography (EtOAc/pet. ether, 1:3) to afford the title compound as ayellow oil (50 mg, 46% yield). MS: (ES, m/z): 312 [M+H]⁺.

Step-2:(S)-4-Formyl-N-hydroxy-2-phenyl-2,3,4,5-tetrahydrobenzo[f][1,4]oxazepine-8-carboxamide

Into a 8-mL vial, was placed a solution of methyl(S)-4-formyl-2-phenyl-2,3,4,5-tetrahydrobenzo[f][1,4]oxazepine-8-carboxylate(50 mg, 0.16 mmol, 1 equiv) in THF/MeOH (4:1, 1.5 mL), then aq. 1N NaOH(0.32 mL, 2 equiv) and NH₂OH (50% in H₂O, 0.31 mL, 30 equiv) were addedsimultaneously. The resulting solution was stirred for 2 h at roomtemperature. The crude product was purified by Prep-HPLC (Column:XBridge RP C18 OBD, 5 μm, 19×150 mm; Mobile Phase A: Water/0.1% formicacid; Mobile Phase B: MeCN; Flow rate: 20 mL/min; Gradient: 30% B to 70%B in 10 min; Detector, UV 254, 220 nm) to afford the title compound as awhite solid (3.8 mg, 8% yield). ¹H-NMR (400 MHz, DMSO-d₆) δ(ppm):11.38-10.89 (br, 1H), 9.23-8.89 (br, 1H), 8.27-8.13 (m, 1H), 7.57-7.49(m, 3H), 7.48-7.38 (m, 5H), 5.01-4.86 (m, 2H), 4.66-4.33 (m, 1H),4.23-4.03 (m, 1H), 3.81-3.58 (m, 1H). MS: (ES, m/z): 313 [M+H]⁺.

Example 27—Preparation ofN⁸-hydroxy-N2,N2-dimethyl-4-(tetrahydro-2H-pyran-4-carbonyl)-2,3,4,5-tetrahydrobenzo[f][1,4]oxazepine-2,8-dicarboxamide

Step-1: tert-Butyl (3-(dim ethylamino)-2-hydroxy-3-oxopropyl)carbamate

Into a 25-mL round-bottom flask, were placed a solution of3-((tert-butoxycarbonyl)amino)-2-hydroxypropanoic acid (1 g, 4.87 mmol,1 equiv) in CH₂Cl₂ (24 mL), dimethylamine hydrochloride (800 mg, 9.81mmol, 2 equiv), and 4-dimethylaminopyridine (1.49 g, 12.21 mmol, 2.5equiv). This was followed by the addition of a solution ofN,N′-dicyclohexylcarbodiimide (1.51 g, 7.33 mmol, 1.5 equiv) in CH₂Cl₂(5 mL) dropwise at room temperature and the resulting solution wasstirred at this temperature for 3 days. The resulting mixture wasconcentrated under vacuum and the residue was re-dissolved with Et₂O (20mL). The precipitated solid was filtered out and the filtrate wasconcentrated under vacuum. The residue was re-dissolved with EtOAc (20mL) and the resulting mixture was washed with aq. NH₄Cl (3×10 mL). Theorganic layer was dried over anhydrous Na₂SO₄, filtered, and the solventwas removed in vacuo to afford the title compound as brown oil (800 mgcrude), which was used without further purification.

Step-2: 3-Amino-2-hydroxy-N,N-dimethylpropanamide

Into a 25-mL round-bottom flask, was placed a solution of tert-butyl(3-(dimethylamino)-2-hydroxy-3-oxopropyl)carbamate (800 mg, 3.44 mmol, 1equiv) in CH₂Cl₂ (8 mL). This was followed by the addition of TFA (3 mL)dropwise with stirring at 0° C. The resulting solution was stirred atroom temperature for 6 h. The solvent was removed in vacuo and theresidue was re-dissolved with H₂O (2 mL). Aqueous 2N NaOH was added toadjust the pH value to 7 and the resulting mixture was concentratedunder vacuum. The residue was dissolved with EtOAc (20 mL) and the solidwas filtered out. The filtrate was concentrated under vacuum to affordthe title compound as light yellow oil (500 mg crude), which was usedwithout further purification.

Step-3: Methyl3-bromo-4-(((3-(dimethylamino)-2-hydroxy-3-oxopropyl)amino)methyl)benzoate

Into a 25-mL round-bottom flask, were placed a solution of3-amino-2-hydroxy-N,N-dimethylpropanamide (500 mg, 3.78 mmol, 2 equiv)in MeCN (8 mL) and K₂CO₃ (389 mg, 2.82 mmol, 1.5 equiv). This wasfollowed by the addition of a solution of methyl3-bromo-4-(bromomethyl)benzoate (618 mg, 2.01 mmol, 1 equiv) in MeCN (5mL) dropwise at room temperature and the resulting solution was stirredat this temperature for 24 h. The solvent was removed in vacuo and theresidue was re-dissolved with H₂O (10 mL). The resulting solution wasextracted with EtOAc (3×10 mL) and the organic layer was washed with H₂O(2×10 mL). The solvent was removed in vacuo and the residue was purifiedby silica gel chromatography (MeOH/CH₂Cl₂, 1:13) to afford the titlecompound as an off-white solid (80 mg, 11% yield). MS: (ES, m/z): 359[M+H]⁺.

Step-4: Methyl2-(dimethylcarbamoyl)-2,3,4,5-tetrahydrobenzo[f][1,4]oxazepine-8-carboxylate

Into a 8-mL sealed tube purged and maintained with an inert atmosphereof nitrogen, were placed a mixture of methyl3-bromo-4-(((3-(dimethylamino)-2-hydroxy-3-oxopropyl)amino)methyl)benzoate(80 mg, 0.22 mmol, 1 equiv) in isopropanol (4 mL), K₂CO₃ (46 mg, 0.33mmol, 1.5 equiv) and CuI (13 mg, 0.07 mmol, 0.3 equiv). The resultingsolution was stirred at 120° C. for 17 h. After cooling to roomtemperature, the resulting mixture was concentrated under vacuum. Waterwas added and the resulting solution was extracted with CH₂Cl₂ (3×10mL). The organic layer was washed with H₂O (2×10 mL), dried overanhydrous Na₂SO₄, and filtered. The solvent was removed in vacuo and theresidue was purified by silica gel chromatography (MeOH/CH₂Cl₂, 1:13) toafford the title compound as a colorless oil (30 mg, 48% yield). MS:(ES, m/z): 279 [M+H]⁺.

Step-5: Methyl2-(dimethylcarbamoyl)-4-(tetrahydro-2H-pyran-4-carbonyl)-2,3,4,5-tetrahydrobenzo[f][1,4]oxazepine-8-carboxylate

Into a 8-mL vial, were placed a solution of oxane-4-carboxylic acid (13mg, 0.10 mmol, 1 equiv) in DMF (1.5 mL), and HATU (45 mg, 0.12 mmol, 1.2equiv). This was followed by the addition of a solution of methyl2-(dimethylcarbamoyl)-2,3,4,5-tetrahydrobenzo[f][1,4]oxazepine-8-carboxylate(30 mg, 0.11 mmol, 1.00 equiv) in DMF (0.5 mL) and DIEA (38 mg, 0.29mmol, 3 equiv). The resulting solution was stirred at room temperaturefor 17 h. Water was added and the resulting solution was extracted withEtOAc (2×10 mL). The organic layer was washed with H₂O (2×10 mL) andbrine (2×10 mL), dried over anhydrous Na₂SO₄, and filtered. The solventwas removed in vacuo and the residue was purified by silica gelchromatography (EtOAc/pet. ether, 1:3) to afford the title compound as ayellow oil (15 mg, 36% yield). MS: (ES, m/z): 391 [M+H]⁺.

Step-6:N⁸—Hydroxy-N²,N²-dimethyl-4-(tetrahydro-2H-pyran-4-carbonyl)-2,3,4,5-tetrahydrobenzo[f][1,4]oxazepine-2,8-dicarboxamide

Into a 8-mL vial, were placed a solution of methyl2-(dimethylcarbamoyl)-4-(tetrahydro-2H-pyran-4-carbonyl)-2,3,4,5-tetrahydrobenzo[f][1,4]oxazepine-8-carboxylate(15 mg, 0.04 mmol, 1 equiv) in THF/MeOH (4:1, 1.5 mL), then NH₂OH (50%in water, 0.1 mL, 30 equiv) and aq. 1N NaOH (0.1 mL, 2 equiv) were addedsimultaneously. The resulting solution was stirred for 2 h at roomtemperature and the crude product was purified by Prep-HPLC (Column:Sunfire Prep C18 OBD, 5 μm, 19×150 mm; Mobile Phase A: Water/0.05% TFA;Mobile Phase B: MeCN; Flow rate: 25 mL/min; Gradient: 5% B to 30% B in 8min; Detector, UV 254, 220 nm) to afford the title compound as a brownoil (3.7 mg, 25% yield). ¹H-NMR (400 MHz, DMSO-d₆) δ(ppm): 11.41-11.11(br, 1H), 7.61-7.42 (m, 1H), 7.40-7.32 (m, 2H), 5.01-4.91 (m, 1H),4.89-4.72 (m, 1H), 4.69-4.42 (m, 1H), 4.19-4.16 (m, 1H), 4.02-3.99 (m,1H), 3.82-3.75 (m, 3H), 3.41-3.30 (m, 2H), 3.12-3.05 (m, 3H), 2.92-2.86(m, 3H), 1.61-1.24 (m, 4H). MS: (ES, m/z): 392[M+H]⁺.

Example 28—Preparation ofN-hydroxy-3,3-dimethyl-4-(1-methylcyclobutane-1-carbonyl)-2,3,4,5-tetrahydrobenzo[f][1,4]oxazepine-8-carboxamide

Step-1: Methyl3-bromo-4-[[(1-hydroxy-2-methylpropan-2-yl)amino]methyl]benzoate

Into a 500-mL round-bottom flask, were placed a solution of2-amino-2-methylpropan-1-ol (11.52 g, 129.24 mmol, 2 equiv) in MeCN (150mL), K₂CO₃ (13.40 g, 97.10 mmol, 1.5 equiv). This was followed by theaddition of a solution of methyl 3-bromo-4-(bromomethyl)benzoate (20 g,64.94 mmol, 1 equiv) in MeCN (50 mL) dropwise with stirring at roomtemperature. The resulting solution was stirred for 16 h at roomtemperature, then concentrated under vacuum. The residue was dilutedwith H₂O (200 mL). The resulting solution was extracted with EtOAc(3×200 mL) and the organic layers combined, washed with H₂O (3×200 mL),and concentrated. The residue was purified by silica gel chromatography(EtOAc/pet. ether, 1:4) to afford the title compound as an off-whitesolid (8.7 g, 42% yield). MS: (ES, m/z): 316 [M+H]⁺.

Step 2: Methyl3,3-dimethyl-2,3,4,5-tetrahydrobenzo[f][1,4]oxazepine-8-carboxylate

Into a 250-mL pressure tank reactor purged and maintained with an inertatmosphere of nitrogen, were placed a solution of methyl3-bromo-4-[[(1-hydroxy-2-methylpropan-2-yl)amino]methyl]benzoate (8.7 g,27.52 mmol, 1 equiv) in isopropanol (150 mL), K₂CO₃ (5.7 g, 41.30 mmol,1.5 equiv) and CuI (1.57 g, 8.26 mmol, 0.3 equiv). The resultingsolution was stirred overnight at 110° C. in an oil bath, thenconcentrated under vacuum. The residue was diluted with H₂O (200 mL).The resulting solution was extracted with EtOAc (3×200 mL) and thecombined organic layers was washed with H₂O (3×200 mL) and concentrated.The residue was purified by silica gel chromatography (EtOAc/pet. ether,1:2) to afford the title compound as a green oil (3.9 g, 60% yield).1H-NMR (400 MHz, DMSO-d6) δ (ppm): 7.63-7.60 (d, J=12.8 Hz, 1H),7.54-7.52 (s, 1H), 7.25-7.23 (d, J=7.6 Hz, 1H), 4.01 (s, 2H), 3.94-3.89(m, 5H), 1.23 (s, 6H). MS: (ES, m/z): 236 [M+H]⁺.

Step-3: Methyl3,3-dimethyl-4-(1-methylcyclobutane-1-carbonyl)-2,3,4,5-tetrahydrobenzo[f][1,4]oxazepine-8-carboxylate

Into a 8-mL vial, were placed a solution of methyl3,3-dimethyl-2,3,4,5-tetrahydrobenzo[f][1,4]oxazepine-8-carboxylate (200mg, 0.85 mmol, 1 equiv) in THE (3 mL), and pyridine (336 mg, 4.25 mmol,5 equiv). This was followed by the addition of a solution of1-methylcyclobutane-1-carbonyl chloride (120 mg, 0.91 mmol, 1 equiv) inTHE (1 mL) dropwise with stirring. The resulting solution was stirredfor 17 h at room temperature, then concentrated under vacuum. Theresidue was diluted with H₂O (10 mL). The resulting solution wasextracted with EtOAc (3×10 mL) and the combined organic layers waswashed with H₂O (3×10 mL) and concentrated. The residue was purified bysilica gel chromatography (EtOAc/pet. ether, 1:3) to afford the titlecompound as a yellow oil (54 mg, 19% yield). MS: (ES, m/z): 332 [M+H]⁺.

Step-4:N-hydroxy-3,3-dimethyl-4-(1-methylcyclobutane-1-carbonyl)-2,3,4,5-tetrahydrobenzo[f][1,4]oxazepine-8-carboxamide

Into a 8-mL sealed tube, was placed a solution of methyl3,3-dimethyl-4-(1-methylcyclobutane-1-carbonyl)-2,3,4,5-tetrahydrobenzo[f][1,4]oxazepine-8-carboxylate(54 mg, 0.16 mmol, 1 equiv) in THF/MeOH (4:1, 2 mL). This was followedby the addition of NH₂OH (50% in water, 0.33 mL, 30 equiv). To this wasadded aq. 1N NaOH (0.33 mL, 2 equiv). The resulting solution was stirredfor 2 h at room temperature. The crude product was purified by Prep-HPLC(Column: XBridge C18 OBD, 5 μm, 19×150 mm; Mobile Phase A: Water/0.05%TFA; Mobile Phase B: MeCN; Flow rate: 20 mL/min; Gradient: 15% B to 41%B in 10 min; Detector, UV 254, 220 nm) to afford the title compound as alight pink solid (13 mg, 24% yield). ¹H-NMR (400 MHz, DMSO-d₆) δ(ppm):11.13 (s, 1H), 7.26-7.19 (m, 3H), 4.51-4.22 (m, 4H), 2.13-2.10 (s, 2H),1.88-1.83 (s, 3H), 1.51-1.45 (m, 7H), 1.34 (s, 1H). MS: (ES, m/z): 333[M+H]⁺.

Example 29—Preparation of4-acetyl-N-hydroxy-3,3-dimethyl-2,3,4,5-tetrahydrobenzo[f][1,4]oxazepine-8-carboxamide

Step-1: Methyl4-acetyl-3,3-dimethyl-2,3,4,5-tetrahydrobenzo[f][1,4]oxazepine-8-carboxylate

Into a 8-mL vial, were placed a solution of methyl3,3-dimethyl-2,3,4,5-tetrahydrobenzo[f][1,4]oxazepine-8-carboxylate (100mg, 0.43 mmol, 1 equiv) in CH₂Cl₂ (2 mL) and Et₃N (172 mg, 1.70 mmol, 4equiv). This was followed by the addition of a solution of acetylchloride (37 mg, 0.47 mmol, 1.1 equiv) in CH₂Cl₂ (0.5 mL) dropwise withstirring at 0° C. The resulting solution was stirred for 18 h at roomtemperature and concentrated under vacuum. The residue was dissolved inin CH₂Cl₂ (30 mL) and washed with H₂O (3×20 mL). The organic layer wasdried over anhydrous MgSO₄, filtered, and concentrated to afford thetitle compound as a green oil (80 mg) which was used without furtherpurification. MS: (ES, m/z): 278 [M+H]⁺.

Step-2:4-Acetyl-N-hydroxy-3,3-dimethyl-2,3,4,5-tetrahydrobenzo[f][1,4]oxazepine-8-carboxamide

Into a 8-mL vial, were placed a solution of methyl4-acetyl-3,3-dimethyl-2,3,4,5-tetrahydrobenzo[f][1,4]oxazepine-8-carboxylate(171 mg, 0.62 mmol, 1 equiv) in THF/MeOH (4:1, 2.5 mL), followed by aq.1N NaOH (1.23 mL, 2 equiv) and NH₂OH (50% in H₂O, 1.22 mL, 30 equiv).The resulting solution was stirred for 3 h at room temperature. Thecrude product was purified by Prep-HPLC (Column: XBridge RP C18 OBD, 5μm, 19×150 mm; Mobile Phase A: Water/0.05% TFA; Mobile Phase B: MeCN;Flow rate: 25 mL/min; Gradient: 4% B to 23% B in 6 min; Detector, UV254, 220 nm) to afford the title compound as a brown solid (41 mg, 24%yield). ¹H-NMR (400 MHz, DMSO-d₆) δ(ppm): 11.13 (br, 1H), 9.01 (br, 1H),7.26 (s, 2H), 7.17 (s, 1H), 4.75 (s, 2H), 4.28 (s, 2H), 1.98 (s, 3H),1.44 (s, 6H). MS: (ES, m/z): 279 [M+H]⁺.

Example 30—Preparation ofN-hydroxy-4-(tetrahydro-2H-pyran-4-carbonyl)-4,5-dihydro-2H-spiro[benzo[f][1,4]oxazepine-3,1′-cyclopropane]-8-carboxamide

Step-1: Methyl3-bromo-4-(((1-(hydroxymethyl)cyclopropyl)amino)methyl)benzoate

Into a 500-mL round-bottom flask, was placed(1-aminocyclopropyl)methanol hydrochloride (6 g, 48.55 mmol, 2 equiv),K₂CO₃ (11 g, 79.59 mmol, 3.5 equiv) in MeCN (120 mL), The mixture wasstirred at room temperature for 10 min. This was followed by theaddition of a solution of methyl 3-bromo-4-(bromomethyl)benzoate (15 g,48.71 mmol, 1 equiv) in MeCN (150 mL) dropwise with stirring at 0° C.over 2h. The resulting solution was stirred overnight at roomtemperature. The resulting mixture was concentrated under vacuum. Theresidue was purified by silica gel chromatography (EtOAc/pet. ether,1:3) to afford the title compound as a yellow oil (7 g, 46% yield). MS:(ES, m/z): 314,316 [M+H]⁺.

Step-2: Methyl4,5-dihydro-2H-spiro[benzo[f][1,4]oxazepine-3,1′-cyclopropane]-8-carboxylate

Into a 40-mL sealed tube purged and maintained with an inert atmosphereof nitrogen, was placed a solution of methyl3-bromo-4-(((1-(hydroxymethyl)cyclopropyl)amino)methyl)benzoate (1.5 g,4.77 mmol, 1 equiv), CuI (273 mg, 1.43 mmol, 0.3 equiv), K₂CO₃ (992 mg,7.18 mmol, 1.5 equiv) in isopropanol (28 mL). The resulting solution wasstirred overnight at 110° C. in an oil bath. The resulting mixture wasconcentrated under vacuum and the residue was diluted with CH₂Cl₂ (150mL). The solids were filtered out and the filtrate was concentratedunder vacuum. The residue was purified by C18 chromatography(MeCN/H₂O+0.05% TFA, 1:4) to afford the title compound as a yellow solid(0.8 g, 72% yield). MS: (ES, m/z): 234 [M+H]⁺.

Step-3: Methyl4-(tetrahydro-2H-pyran-4-carbonyl)-4,5-dihydro-2H-spiro[benzo[f][1,4]oxazepine-3,1′-cyclopropane]-8-carboxylate

Into a 100-mL round-bottom flask, was placed a solution of methyl4,5-dihydro-2H-spiro[benzo[f][1,4]oxazepine-3,1′-cyclopropane]-8-carboxylate(130 mg, 0.56 mmol, 1 equiv) in CH₂Cl₂ (10 mL), and pyridine (1 mL). Themixture was stirred for 1 h followed by addition of oxane-4-carbonylchloride (400 mg, 2.69 mmol, 4.83 equiv). The resulting mixture wasstirred overnight at room temperature and then concentrated undervacuum. The residue was purified by silica gel chromatography(EtOAc/pet. ether, 1:1) to afford the title compound as a yellow solid(60 mg, 31% yield). MS: (ES, m/z): 346 [M+H]⁺.

Step-4:N-Hydroxy-4-(tetrahydro-2H-pyran-4-carbonyl)-4,5-dihydro-2H-spiro[benzo[f][1,4]oxazepine-3,1′-cyclopropane]-8-carboxamide

Into a 50-mL round-bottom flask, was placed methyl4-(tetrahydro-2H-pyran-4-carbonyl)-4,5-dihydro-2H-spiro[benzo[f][1,4]oxazepine-3,1′-cyclopropane]-8-carboxylate(60 mg, 0.17 mmol, 1 equiv), NH₂OH (50% in water, 0.50 mL, 44.56 equiv),aq. 1N NaOH (1.5 mL, 8.82 equiv), and THF/MeOH (4:1, 3 mL). Theresulting solution was stirred overnight at room temperature. The crudeproduct was purified by Prep-HPLC (Column: XBridge RP C18 OBD, 5 μm,19×150 mm; Mobile Phase A: Water/0.05% formic acid; Mobile Phase B:MeCN; Flow rate: 20 mL/min; Gradient: 12% B to 34% B in 9 min; Detector,UV 254 nm) to afford the title compound as a white solid (21.5 mg, 32%yield). ¹H-NMR (300 MHz, DMSO-d₆) δ(ppm): 11.18 (br, 1H), 7.57-7.29 (m,3H), 4.61 (s, 2H), 3.82-3.76 (m, 4H), 3.57-3.24 (m, 2H), 3.23-2.75 (m,1H), 1.48-0.85 (m, 8H). MS: (ES, m/z): 347 [M+H]⁺.

Example 31—Preparation of(R)-4-acetyl-N-hydroxy-3-isopropyl-2,3,4,5-tetrahydrobenzo[f][1,4]oxazepine-8-carboxamide

Step-1: Methyl(R)-3-bromo-4-(((1-hydroxy-3-methylbutan-2-yl)amino)methyl)benzoate

Into a 1-L round-bottom flask, was placed a solution of(R)-2-amino-3-methylbutan-1-ol (23.33 g, 226.15 mmol, 2 equiv) in MeCN(300 mL). This was followed by the addition of a solution of methyl3-bromo-4-(bromomethyl)benzoate (35 g, 113.65 mmol, 1 equiv) in MeCN(200 mL) dropwise with stirring. The resulting solution was stirred for15 h at room temperature, then concentrated under vacuum. The residuewas diluted with H₂O (300 mL), extracted with EtOAc (3×200 mL) and thecombined organic layers were concentrated. The residue was purified bysilica gel chromatography (EtOAc/pet. ether, 1:4) to afford the titlecompound as an off-white solid (22 g, 59% yield). MS: (ES, m/z): 330[M+H]⁺.

Step-2: Methyl(R)-3-isopropyl-2,3,4,5-tetrahydrobenzo[f][1,4]oxazepine-8-carboxylate

Into a 500-mL pressure tank reactor purged and maintained with an inertatmosphere of nitrogen, were placed a solution of methyl(R)-3-bromo-4-(((1-hydroxy-3-methylbutan-2-yl)amino)methyl)benzoate (13g, 39.37 mmol, 1 equiv) in isopropanol (260 mL), K₂CO₃ (8.16 g, 59.13mmol, 1.5 equiv) and CuI (2.25 g, 11.84 mmol, 0.3 equiv). The resultingmixture was stirred for 24 h at 110° C. in an oil bath and thenconcentrated under vacuum. The residue was diluted with H₂O (300 mL),extracted with CH₂Cl₂ (3×300 mL). The combined organic layers werewashed with H₂O (3×300 mL) and concentrated. The residue was purified bysilica gel chromatography (EtOAc/pet. ether, 1:1) to afford the titlecompound as a yellow oil (4.9 g, 50% yield). 1H-NMR (400 MHz, DMSO-d6) δ(ppm): 7.66-7.64 (d, J=8.0 Hz, 1H), 7.57 (s, 1H), 7.30-7.28 (d, J=8.0Hz, 1H), 4.52-4.22 (m, 1H), 4.07-3.94 (m, 2H), 3.94-3.84 (m, 3H),3.81-3.62 (m, 1H), 1.92-1.72 (m, 1H) 1.09-0.91 (m, 6H). MS: (ES, m/z):250 [M+H]⁺.

Step-3: Methyl(R)-4-acetyl-3-isopropyl-2,3,4,5-tetrahydrobenzo[f][1,4]oxazepine-8-carboxylate

Into a 8-mL vial, were placed a solution of methyl(R)-3-isopropyl-2,3,4,5-tetrahydrobenzo[f][1,4]oxazepine-8-carboxylate(150 mg, 0.60 mmol, 1 equiv) in CH₂Cl₂ (3 mL) and Et₃N (243 mg, 2.40mmol, 4 equiv). This was followed by the addition of a solution ofacetyl chloride (52 mg, 0.66 mmol, 1.1 equiv) in CH₂Cl₂ (0.5 mL)dropwise with stirring at 0° C. The resulting solution was stirred for18 h at room temperature and then concentrated under vacuum. The residuewas dissolved in CH₂Cl₂ (30 mL), washed with H₂O (3×20 mL), dried overanhydrous magnesium sulfate, filtered, and concentrated to afford thetitle compound as a yellow oil (120 mg, 68% yield). MS: (ES, m/z): 292[M+H]⁺.

Step-4:(R)-4-Acetyl-N-hydroxy-3-isopropyl-2,3,4,5-tetrahydrobenzo[f][1,4]oxazepine-8-carboxamide

Into a 8-mL vial, was placed a solution of methyl(R)-4-acetyl-3-isopropyl-2,3,4,5-tetrahydrobenzo[f][1,4]oxazepine-8-carboxylate(120 mg, 0.41 mmol, 1 equiv) in THF/MeOH (4:1, 2 mL), followed by theaddition of aq. 1N NaOH (0.82 mL, 2 equiv) and NH₂OH (50% in H₂O, 0.82mL, 30 equiv). The resulting solution was stirred for 3 h at roomtemperature. The crude product was purified by Prep-HPLC (Column SunfirePrep C18 OBD, 5 μm, 19×150 mm; Mobile Phase A: Water/0.05% TFA; MobilePhase B: MeCN; Flow rate: 25 mL/min; Gradient: 5% B to 40% B in 7 min;Detector, UV 254, 220 nm) to afford the title compound as an off-whitesolid (81 mg, 67% yield). ¹H-NMR (400 MHz, DMSO-d₆) δ(ppm): 11.14 (br,1H), 7.37-7.19 (m, 3H), 4.95-4.90 (d, J=15.0 Hz, 0.3H), 4.80-4.75 (d,J=15.0 Hz, 0.6H), 4.58-4.47 (m, 1.4H), 4.36-4.22 (m, 2H), 3.88-3.81 (m,0.7H), 2.08-2.01 (m, 1H), 1.95-1.83 (m, 3H), 1-0.98 (m, 6H). MS: (ES,m/z): 293 [M+H]⁺.

TABLE 17 The following compounds were prepared according to the methodof Example 31, using (S)-2-amino-3-methylbutan-1-ol. Found Structure M +H ¹H-NMR (400 MHz, DMSO-d₆) δ (ppm)

(ES, m/z): 293 [M + H]⁺ 11.13 (s, 1H), 7.41-7.11 (m, 3H), 4.98-4.72 (m,1H), 4.62-4.41 (m, 2H), 4.39-4.17 (m, 2H), 2.11-1.88 (m, 4H), 1.08-0.81(m, 6H)

(ES, m/z): 363 [M + H]⁺ 11.17 (br, 1H), 9.01 (br, 1H), 7.43-7.17 (m,3H), 4.92-4.77 (m, 2H), 4.57-4.55 (m, 0.6H), 4.38-4.28 (m, 2.4H),4.08-4.01 (m, 0.4H), 3.85-3.83 (m, 1H), 3.81-3.65 (m, 1H), 3.43-3.33 (m,1H), 3.14-3.11 (m, 0.6H), 2.95-2.92 (m, 0.4H), 2.76 (m, 0.6H), 2.01-1.72(m, 1H), 1.70-1.23 (m, 3H), 1.02-0.81 (m, 6H), 0.71-0.68 (m, 1H)

Example 32—Preparation of(R)—N-hydroxy-3-isopropyl-4-(1-methylcyclobutane-1-carbonyl)-2,3,4,5-tetrahydrobenzo[f][1,4]oxazepine-8-carboxamide

Step-1: Methyl(R)-3-isopropyl-4-(1-methylcyclobutane-1-carbonyl)-2,3,4,5-tetrahydrobenzo[f][1,4]oxazepine-8-carboxylate

Into a 8-mL vial, were placed a solution of methyl(R)-3-isopropyl-2,3,4,5-tetrahydrobenzo[f][1,4]oxazepine-8-carboxylate(100 mg, 0.40 mmol, 1 equiv) in DMF (2 mL), HATU (184 mg, 0.48 mmol,1.20 equiv), 1-methylcyclobutane-1-carboxylic acid (46 mg, 0.40 mmol, 1equiv) and DIEA (156 mg, 1.21 mmol, 3 equiv). The resulting solution wasstirred for 19 h at room temperature. The reaction was diluted with H₂O(10 mL) and extracted with EtOAc (3×10 mL). The combined organic layerswere washed with H₂O (3×10 mL) and concentrated. The residue waspurified by silica gel chromatography (EtOAc/pet. ether, 1:4) to affordthe title compound as a brown oil (75 mg, 54% yield). MS: (ES, m/z): 346[M+H]⁺.

Step-2:(R)—N-hydroxy-3-isopropyl-4-(1-methylcyclobutane-1-carbonyl)-2,3,4,5-tetrahydrobenzo[f][1,4]oxazepine-8-carboxamide

Into a 8-mL vial, was placed a solution of methyl(R)-3-isopropyl-4-(1-methylcyclobutane-1-carbonyl)-2,3,4,5-tetrahydrobenzo[f][1,4]oxazepine-8-carboxylate(75 mg, 0.22 mmol, 1 equiv) in THF/MeOH (4:1, 2 mL), followed by theaddition of NH₂OH (50% in water, 0.43 mL, 30 equiv) and aq. 1N NaOH(0.44 mL, 2 equiv). The resulting solution was stirred for 2 h at roomtemperature. The crude product was purified by Prep-HPLC (Column SunfirePrep C18 OBD, 5 μm, 19×150 mm; Mobile Phase A: Water/0.05% TFA; MobilePhase B: MeCN; Flow rate: 25 mL/min; Gradient: 5% B to 70% B in 7 min;Detector, UV 254, 220 nm) to afford the title compound as a pink solid(45 mg, 60% yield). ¹H-NMR (400 MHz, DMSO-d₆) δ(ppm): 11.39-10.80 (br,1H), 7.40-7.09 (m, 3H), 4.80-4.63 (m, 1H), 4.41-4.29 (m, 2H), 4.25-4.15(m, 1H), 2.35-2.22 (m, 1H), 1.98-1.60 (m, 5H), 1.57-1.43 (m, 1H),1.39-1.21 (m, 3H), 1.08-0.72 (m, 6H). MS: (ES, m/z): 347 [M+H]⁺.

TABLE 18 The following compounds were prepared according to the methodof Example 32, using methyl(S)-3-isopropy1-2,3,4,5-tetrahydrobenzo[f][1,4]oxazepine-8-carboxylate.Found Structure M + H ¹H-NMR (400 MHz, DMSO-d₆) δ (ppm)

(ES, m/z): 347 [M + H]⁺ 11.15 (br, 1H), 7.39-7.19 (m, 3H), 4.75-4.71 (d,J = 17.6 Hz, 1H), 4.66-4.53 (m, 1H), 4.41-4.29 (m, 2H), 4.23-4.17 (m,1H), 2.37-2.27 (m, 1H), 2.01-1.59 (m, 5H), 1.59- 1.42 (m, 1H), 1.39-1.22(m, 3H), 0.99-0.89 (m, 3H), 0.87-0.72 (m, 3H)

(ES, m/z): 378 [M + H]⁺ 11.13 (br, 1H), 7.71 (br, 1H), 7.35-7.29 (m,2H), 7.22-7.17 (m, 1H), 4.98-4.89 (m, 0.3H), 4.81-4.55 (m, 2H),4.34-4.28 (m, 2H), 3.98-3.87 (m, 0.3H), 3.76-3.72 (m, 1.3H), 3.66-3.63(m, 0.7H), 3.20-3.12 (m, 2H), 2.49-2.30 (m, 1H), 2.27-2.09 (m, 0.3H),1.89-1.79 (m, 2.7H), 1.54-1.38 (m, 1H), 1.32-1.28 (m, 1H), 1.14-1.09 (m,1H), 0.99-0.90 (m, 4H), 0.86-0.80 (m, 3H)

Example 33—Preparation of(R)-4-formyl-N-hydroxy-3-methyl-2,3,4,5-tetrahydrobenzo[f][1,4]oxazepine-8-carboxamide

Step-1: Methyl(R)-3-bromo-4-(((1-hydroxypropan-2-yl)amino)methyl)benzoate

Into a 250-mL round-bottom flask, was placed (R)-2-aminopropan-1-ol(3.64 g, 48.46 mmol, 1 equiv), MeCN (120 mL), K₂CO₃ (10.05 g, 72.72mmol, 1.5 equiv) and methyl 3-bromo-4-(bromomethyl)benzoate (15 g, 48.71mmol, 1 equiv). The resulting solution was stirred for 3 h at roomtemperature. The resulting mixture was concentrated under vacuum anddiluted with water (200 mL). The resulting solution was extracted withEtOAc (2×300 mL), dried and concentrated under vacuum. The residue waspurified by silica gel chromatography (EtOAc/pet. ether, 1:5) to affordthe title compound as an off-white solid (6.5 g, 44% yield). MS: (ES,m/z): 302 [M+H]⁺.

Step-2: Methyl(R)-3-methyl-2,3,4,5-tetrahydrobenzo[f][1,4]oxazepine-8-carboxylate

Into a 100-mL pressure tank reactor purged and maintained with an inertatmosphere of nitrogen, was placed methyl(R)-3-bromo-4-(((1-hydroxypropan-2-yl)amino)methyl)benzoate (4 g, 13.24mmol, 1 equiv), isopropanol (80 mL), K₂CO₃ (2.67 g, 19.32 mmol, 1.5equiv) and CuI (760 mg, 3.99 mmol, 0.3 equiv). The resulting solutionwas stirred for 16 h at 110° C. in an oil bath. The resulting mixturewas concentrated under vacuum and diluted with water (200 mL). Theresulting solution was extracted with CH₂Cl₂ (2×200 mL), dried andconcentrated under vacuum. The residue was purified by silica gelchromatography (EtOAc/pet. ether, 1:2) to afford the title compound as ayellow oil (2.1 g, 72% yield). ¹H-NMR (400 MHz, DMSO-d₆) δ(ppm):9.30-9.15 (br, 1H), 7.74-7.72 (d, J=8.0 Hz, 1H), 7.62-7.57 (m, 2H),4.47-4.36 (m, 3H), 3.85-3.79 (s, 3H), 3.77-3.75 (m, 2H), 1.23-1.22 (d,J=6.0 Hz, 2H). MS: (ES, m/z): 222 [M+H]⁺.

Step-3: Methyl(R)-4-formyl-3-methyl-2,3,4,5-tetrahydrobenzo[f][1,4]oxazepine-8-carboxylate

Into a 8-mL vial, was placed methyl(R)-3-methyl-2,3,4,5-tetrahydrobenzo[f][1,4]oxazepine-8-carboxylate (94mg, 0.42 mmol, 1 equiv) and ethyl formate (2 mL, 1 equiv). The resultingsolution was stirred for 20 h at 57° C. in an oil bath. The mixture wasconcentrated under vacuum to afford the title compound as yellow oil(100 mg) which was used without further purification. MS: (ES, m/z): 250[M+H]⁺.

Step-4:(R)-4-Formyl-N-hydroxy-3-methyl-2,3,4,5-tetrahydrobenzo[f][1,4]oxazepine-8-carboxamide

Into a 8-mL vial, was placed methyl(R)-4-formyl-3-methyl-2,3,4,5-tetrahydrobenzo[f][1,4]oxazepine-8-carboxylate(100 mg, 0.40 mmol, 1 equiv) and THF/MeOH (4:1, 2.5 mL). To this wasadded aq. 1N NaOH (0.8 mL, 2 equiv) and NH₂OH (50% in H₂O, 0.8 mL, 30equiv). The resulting solution was stirred for 3 h at room temperature.The crude product was purified by Prep-HPLC (Column: Sunfire Prep C18OBD, 5 μm, 19×150 mm; Mobile Phase A: Water/0.05% TFA; Mobile Phase B:MeCN; Flow rate: 0.7 mL/min; Gradient: 5% B to 24% B in 6 min; Detector:UV 254, 220 nm) to afford the title compound as an off-white solid (66mg, 45% yield). ¹H-NMR (400 MHz, DMSO-d₆) δ(ppm): 11.14 (br, 1H),8.15-8.13 (d, J=9.6 Hz, 1H), 7.34-7.21 (m, 3H), 4.91-4.79 (q, 1H),4.68-4.43 (m, 2H), 4.39-4.11 (m, 3H), 1.23-1.09 (m, 3H). MS: (ES, m/z):251 [M+H]⁺.

Example 34—Preparation of(R)—N-hydroxy-3-methyl-4-(1-methylcyclobutane-1-carbonyl)-2,3,4,5-tetrahydrobenzo[f][1,4]oxazepine-8-carboxamide

Step-1: Methyl(R)-3-methyl-4-(1-methylcyclobutane-1-carbonyl)-2,3,4,5-tetrahydrobenzo[f][1,4]oxazepine-8-carboxylate

Into a 20-mL vial, was placed a solution of methyl(R)-3-methyl-2,3,4,5-tetrahydrobenzo[f][1,4]oxazepine-8-carboxylate (100mg, 0.45 mmol, 1 equiv) in DMF (13 mL), 1-methylcyclobutane-1-carboxylicacid (80 mg, 0.70 mmol, 1.2 equiv), HATU (150 mg, 0.39 mmol, 1.2 equiv)and DIEA (150 mg, 1.16 mmol, 3 equiv). The resulting solution wasstirred for 10 h at room temperature. The resulting mixture wasconcentrated under vacuum. The residue was purified by silica gelchromatography (EtOAc/pet. ether, 1:5) to afford the title compound as alight yellow oil (80 mg, 56% yield). MS: (ES, m/z): 318 [M+H]⁺.

Step-2:(R)—N-hydroxy-3-methyl-4-(1-methylcyclobutane-1-carbonyl)-2,3,4,5-tetrahydrobenzo[f][1,4]oxazepine-8-carboxamide

Into a 10-mL round-bottom flask, was placed a solution of methyl(R)-3-methyl-4-(1-methylcyclobutane-1-carbonyl)-2,3,4,5-tetrahydrobenzo[f][1,4]oxazepine-8-carboxylate(80 mg, 0.25 mmol, 1 equiv) in THF/MeOH (4:1, 2.5 mL). This was followedby the addition of aq. 1N NaOH (0.50 mL, 2 equiv) and NH₂OH (50% inwater, 0.50 mL, 30 equiv). The resulting solution was stirred for 3 h atroom temperature. The crude product was purified by Prep-HPLC (Column:XBridge XP C18 OBD, 5 μm, 19×150 mm; Mobile Phase A: Water/0.05% TFA;Mobile Phase B: MeCN; Flow rate: 0.7 mL/min; Gradient: 12% B to 47% B in12 min; Detector: UV 254, 220 nm) to afford the title compound as alight yellow solid (41 mg, 51% yield). ¹H-NMR (400 MHz, DMSO-d₆) δ(ppm):11.13 (br, 1H), 9.01 (br, 1H), 7.32-7.18 (m, 3H), 4.85-4.68 (m, 1.5H),4.41-4.37 (m, 0.5H), 4.28-4.06 (m, 3H), 2.50-2.43 (m, 0.6H), 2.32-2.25(m, 1H), 1.96-1.73 (m, 3H), 1.59-1.47 (m, 1H), 1.34 (s, 1.4H), 1.27 (s,1.5H), 1.21-1.20 (m, 1.4H), 1-0.99 (m, 1.5H). MS: (ES, m/z): 319 [M+H]⁺.

Example 35—Preparation of(R)-4-acetyl-N-hydroxy-3-methyl-2,3,4,5-tetrahydrobenzo[f][1,4]oxazepine-8-carboxamide

Step-1: Methyl(R)-4-acetyl-3-methyl-2,3,4,5-tetrahydrobenzo[f][1,4]oxazepine-8-carboxylate

Into a 8-mL vial, were placed a solution of methyl(R)-3-methyl-2,3,4,5-tetrahydrobenzo[f][1,4]oxazepine-8-carboxylate (80mg, 0.24 mmol, 1 equiv) in CH₂Cl₂ (2 mL) and Et₃N (96 mg, 0.95 mmol, 4equiv), followed by the addition of a solution of acetyl chloride (20mg, 0.25 mmol, 1.1 equiv) in CH₂Cl₂ (1 mL) dropwise at 0° C. Theresulting solution was stirred for 18 h at room temperature. Theresulting mixture was concentrated under vacuum to afford the titlecompound as a brown oil (60 mg) which was used without furtherpurification. MS: (ES, m/z): 264 [M+H]⁺.

Step-2:(R)-4-Acetyl-N-hydroxy-3-methyl-2,3,4,5-tetrahydrobenzo[f][1,4]oxazepine-8-carboxamide

Into a 8-mL vial, were placed a solution of methyl(R)-4-acetyl-3-methyl-2,3,4,5-tetrahydrobenzo[f][1,4]oxazepine-8-carboxylate(60 mg, 0.23 mmol, 1 equiv) in THF/MeOH (4:1, 1.5 mL), followed by theaddition of aq. 1N NaOH (0.45 mL, 2 equiv) and NH₂OH (50% in water, 0.44mL, 30 equiv). The resulting solution was stirred for 14 h at roomtemperature. The crude product was purified by Prep-HPLC (Column:Sunfire Prep C18 OBD, 5 μm, 19×150 mm; Mobile Phase A: Water/0.05% TFA;Mobile Phase B: MeCN; Flow rate: 25 mL/min; Gradient: 4% B to 18% B in 6min; Detector: UV 254, 220 nm) to afford the title compound as a brownoil (12 mg, 20% yield). ¹H-NMR (400 MHz, DMSO-d₆) δ(ppm): 11.17 (br,1H), 9 (s, 1H), 7.32-7.16 (m, 4H), 4.96-4.79 (m, 2H), 4.53-4.42 (m, 1H),4.36-4.12 (m, 3H), 2.03 (s, 1H), 1.20 (s, 2H), 1.21-1.19 (m, 1H),1.18-1.08 (m, 2H). MS: (ES, m/z): 265 [M+H]⁺.

Example 36—Preparation of(S)—N-hydroxy-3-methyl-4-(4-methyltetrahydro-2H-pyran-4-carbonyl)-2,3,4,5-tetrahydrobenzo[f][1,4]oxazepine-8-carboxamide

Step-1: Methyl(S)-3-bromo-4-(((1-hydroxypropan-2-yl)amino)methyl)benzoate

Into a 500-mL round-bottom flask, was placed a solution of methyl3-bromo-4-(bromomethyl)benzoate (10 g, 32.47 mmol, 1 equiv) in THE (150mL), (S)-2-aminopropan-1-ol (2.4 g, 31.95 mmol, 1 equiv) and K₂CO₃ (6.7g, 1.5 equiv). The resulting solution was stirred for 3 h at roomtemperature, then concentrated under vacuum. The residue was washed withEtOAc/pet. ether (1:10, 20 mL) to afford the title compound as anoff-white solid (5 g, 51% yield). MS: (ES, m/z): 302 [M+H]⁺.

Step-2: Methyl(S)-3-methyl-2,3,4,5-tetrahydrobenzo[f][1,4]oxazepine-8-carboxylate

Into a 100-mL round-bottom flask purged and maintained with an inertatmosphere of nitrogen, was placed a solution of methyl(S)-3-bromo-4-(((1-hydroxypropan-2-yl)amino)methyl)benzoate (3.2 g,10.59 mmol, 1 equiv) in isopropanol (35 mL), K₂CO₃ (2.20 g, 15.92 mmol,1.5 equiv) and CuI (610 mg, 3.20 mmol, 0.3 equiv). The resultingsolution was stirred for 19 h at 110° C. in an oil bath. The resultingmixture was concentrated under vacuum, diluted with EtOAc (300 mL), andwashed with H₂O (3×100 mL). The organic phase was concentrated and theresidue was purified by silica gel chromatography (EtOAc/pet. ether,1:4) to afford the title compound as a light yellow oil (1 g, 43%yield). ¹H-NMR (400 MHz, DMSO-d₆) δ(ppm): 7.57-7.50 (m, 1H), 7.45 (s,1H), 7.35-7.29 (m, 1H), 4.27-4.19 (m, 1H), 3.99-3.81 (m, 5H), 3.37-3.21(m, 2H), 3.17-3.10 (s, 1H), 1.05-0.94 (d, J=6.4 Hz, 3H). MS: (ES, m/z):222 [M+H]⁺.

Step-3: Methyl(S)-3-methyl-4-(4-methyltetrahydro-2H-pyran-4-carbonyl)-2,3,4,5-tetrahydrobenzo[f][1,4]oxazepine-8-carboxylate

Into a 8-mL vial, was placed methyl(S)-3-methyl-2,3,4,5-tetrahydrobenzo[f][1,4]oxazepine-8-carboxylate (100mg, 0.45 mmol, 1 equiv) in DMF (2.0 mL), HATU (205 mg, 0.54 mmol, 1.2equiv), 4-methyltetrahydro-2H-pyran-4-carboxylic acid (77.8 mg, 0.54mmol, 1.2 equiv), and DIEA (174 mg, 1.35 mmol, 3 equiv). The resultingmixture was stirred overnight at room temperature. The mixture wasdiluted with H₂O (20 mL) and extracted with EtOAc (3×20 mL). The organiclayer was washed with H₂O (3×20 mL), dried over anhydrous Na₂SO₄,filtered, and concentrated. The residue was purified by silica gelchromatography (EtOAc/pet. ether, 2:3) to afford the title compound asan orange oil (52 mg, 33% yield). MS: (ES, m/z): 348 [M+H]⁺.

Step-4:(S)—N-Hydroxy-3-methyl-4-(4-methyltetrahydro-2H-pyran-4-carbonyl)-2,3,4,5-tetrahydrobenzo[f][1,4]oxazepine-8-carboxamide

Into a 8-mL vial, was placed methyl(S)-3-methyl-4-(4-methyltetrahydro-2H-pyran-4-carbonyl)-2,3,4,5-tetrahydrobenzo[f][1,4]oxazepine-8-carboxylate(52 mg, 0.15 mmol, 1 equiv) in THF/MeOH (4:1, 2.0 mL). Then aq. 1N NaOH(0.3 mL, 2 equiv) and NH₂OH (50% in H₂O, 0.3 mL, 30 equiv) were addedsimultaneously. The resulting solution was stirred for 2 h at roomtemperature. The crude product was purified by Prep-HPLC (Column:Sunfire C18, 5 μm, 19×150 mm; Mobile Phase A: Water/0.05% TFA; MobilePhase B: MeCN; Flow rate: 25 mL/min; Gradient: 5% B to 35% B in 8 min;Detector, UV 254, 220 nm) to afford the title compound as an orangesolid (20.7 mg, 30% yield). ¹H-NMR (400 MHz, DMSO-d₆) δ(ppm): 11.13 (s,1H), 9.02-8.93 (br, 1H), 7.31-7.25 (s, 2H), 7.21-7.17 (s, 1H), 4.80-4.87(m, 3H), 4.25-4.10 (m, 2H), 3.59-3.55 (m, 2H), 3.41-3.36 (m, 2H),1.96-1.93 (d, 2H), 1.47-1.35 (m, 2H), 1.210 (s, 3H), 1.11 (s, 3H). MS:(ES, m/z): 349 [M+H]⁺.

TABLE 19 The following compounds were prepared according to the methodof Example 36, with these modifications: (1) In Step 3, the solvent canbe DMF, DMA, or CH₂C1₂; (2) In Step 3, the base can be DIEA or Et₃N; (3)In Step 4, the Prep-HPLC column can be Sunfire C18, 5 μm, 19 × 150 mmusing TFA, formic acid, or NH₄HCO₃ as the additive to the water MobilePhase A; or the column XBridge RP C18 OBD, 5 μm, 19 × 150 mm using TFA,formic acid, or NH₄HCO₃ as the additive to the water Mobile Phase A.Found Structure M + H ¹H-NMR (300 or 400 MHz, DMSO-d₆) δ (ppm)

(ES, m/z): 319 [M + H]⁺ 11.14 (s, 1H), 7.32-7.19 (m, 3H), 4.85-4.77 (m,2H), 4.42-4.37 (m, 1H), 4.29-4.07 (m, 3H), 2.29-2.26 (d, J = 9 Hz 1H),1.96-1.90 (m, 4H), 1.87-1.81 (m, 1H), 1.49-1.46 (m, 3H), 1.34-1.27 (m,2H), 1.01-0.98 (m, 2H)

(ES, m/z): 383 [M + H]⁺ 11.15 (br, 1H), 9.50-8.47 (br, 1H), 7.44- 7.16(m, 3H), 4.94-4.87 (m, 1H), 4.67-4.63 (m, 1H), 4.52-4.48 (m, 1H),4.30-4.16 (m, 2H), 3.28-2.92 (m, 5H), 2.11-1.97 (m, 2.5H), 1.87-1.76 (m,1H), 1.30-1.27 (m, 0.5H), 1.21-1.05 (m, 3H)

(ES, m/z): 349 [M + H]⁺ 11.14 (br, 1H), 9.01 (br, 1H), 7.37-7.29 (m,1H), 7.38-7.19 (m, 1H), 7.18 (s, 1H), 5.14- 4.93 (m, 1H), 4.85-4.49 (m,2H), 4.27-4.10 (m, 2H), 3.02 (s, 1.4H), 2.61 (s, 1.6H), 2.11-1.78 (m,3H), 1.69-1.39 (m, 5H), 1.21 (m, 1.4H), 1.05 (m, 1.6H)

(ES, m/z): 369 [M + H]⁺ 11.23-11.03 (m, 1H), 9.21-8.76 (br, 1H),7.49-7.12 (m, 3H), 5.01-4.79 (m, 2H), 4.77- 4.43 (m, 1H), 4.38-4.09 (m,2H), 3.79-3.61 (m, 1H), 3.41-3.29 (m, 1H), 3.27-3.05 (m, 2H), 2.97-2.81(m, 1H), 2.39-2.01 (m, 1H), 1.89-1.52 (m, 1H), 1.29-1.01 (m, 3H)

(ES, m/z): 335 [M + H]⁺ 11.15 (br, 1H), 7.34-7.16 (m, 3H), 4.85-4.67 (m,2H), 4.53-4.49 (m, 1H), 4.25-4.12 (m, 2H), 2.97 (s, 1H), 2.68-2.54 (m,2H), 2.50- 2.33 (m, 1H), 2.22-2.15 (m, 2H), 2.02-1.89 (m, 1H), 1.75-1.70(m, 1H), 1.49-1.44 (m, 1H), 1.19-1.06 (m, 3H)

(ES, m/z): 321 [M + H]⁺ 11.16-11.14 (br, 1H), 9.29-8.71 (br, 1H),7.34-7.27 (m, 2H), 7.21-7.20 (m, 1H), 4.94-4.71 (m, 3H), 4.48-4.44 (d, J= 16.0 Hz, 1H), 4.35-4.06 (m, 4H), 3.79- 3.75 (d, J = 16.0 Hz, 1H),1.54-1.50 (d, J = 16.0 Hz, 3H), 1.20-1.05 (m, 3H)

(ES, m/z): 307 [M + H]⁺ 11.21-10.95 (s, 1H), 9.31-8.65 (br, 1H),7.39-7.25 (m, 2H), 7.24-7.12 (s, 1H), 4.98-4.81 (m, 2H), 4.78-4.61 (m,2H), 4.58-4.34 (m, 1H), 4.31-4.13 (m, 3H), 4.11-3.85 (m, 2H), 1.19-1.01(m, 3H)

(ES, m/z): 355 [M + H]⁺ 11.23-10.98 (s, 1H), 9.39-8.63 (br, 1H),7.52-7.26 (m, 2H), 7.23-7.13 (m, 1H), 4.98-4.73 (m, 1H), 4.62-4.29 (m,4H), 4.25-4.17 (m, 1H), 4.09-3.87 (m, 2H), 3.77-3.63 (m, 1H), 3.59-3.45(m, 1H), 1.31-1.02 (m, 3H)

(ES, m/z): 321 [M + H]⁺ 11.13 (br, 1H), 8.97 (br, 1H), 7.39-7.10 (m,3H), 5.03-4.51 (m, 3H), 4.32-4.10 (m, 2H), 3.18 (s, 1.8H), 2.69 (s,1.2H), 1.34-0.96 (m, 5H), 0.85-0.60 (m, 2H)

(ES, m/z): 335 [M + H]⁺ 11.02 (br, 1H), 9.37-8.41 (br, 1H), 7.42- 7.15(m, 3H), 4.92-4.70 (m, 2H), 4.48- 4.44 (m, 1H), 4.28-4.18 (m, 2H), 3.86-3.83 (m, 2H), 3.67-3.64 (m, 1H), 3.41- 3.35 (m, 1.5H), 3.15-3.09 (m,0.5H), 2.87-2.77 (m, 1H), 1.72-1.58 (m, 1H), 1.56-1.49 (m, 1H),1.42-1.35 (m, 1H), 1.21-1.19 (m, 1H), 1.04-1.03 (m, 2H)

(ES, m/z): 323 [M + H]⁺ 11.31-10.88 (s, 1H), 7.38-7.29 (m, 1H),7.27-7.12 (m, 2H), 5.35-5.09 (m, 1H), 4.92-4.45 (m, 2H), 4.28-4.09 (m,2H), 3.21-2.98 (m, 1H), 2.87-2.67 (m, 2H), 1.39-1.27 (m, 4H), 1.25-1.19(m, 1H), 1.17-1.11 (m, 2H), 1.09-0.99 (m, 2H)

(ES, m/z): 365 [M + H]⁺ 11.15-11.21 (d, 2H), 9.05 (br, 1H), 7.34- 7.17(m, 3H), 5.36-5.22 (m, 1H), 4.87- 4.49 (m, 2H), 4.22-4.09 (m, 2H), 3.61-3.46 (m, 4H), 2.68-2.50 (m, 3H), 1.93- 1.56 (m, 4H), 1.23-1.06 (m, 3H)

(ES, m/z): 363 [M + H]⁺ 11.15 (m, 1H), 8.96 (br, 1H), 7.37-7.14 (m, 3H),5.42-5.21 (m, 1H), 4.84-4.45 (m, 2H), 4.23-4.10 (m, 2H), 3.06 (s, 1.4H),2.67 (s, 1.6H), 1.99-1.58 (m, 3H), 1.57-1.29 (m, 6H), 1.23 (d, J = 6.4Hz, 1.4H), 1.22-1.11 (m, 1H), 1.03 (d, J = 6.4 Hz, 1.6H)

(ES, m/z): 361 [M + H]⁺ 11.16 (br, 1H), 7.43-7.15 (m, 3H), 4.91-4.71 (m,2H), 4.47-4.43 (m, 1H), 4.31-4.14 (m, 4H), 4.07-4.06 (d, J = 4.0 Hz,1H), 2.96 (m, 1H), 1.92- 1.72 (m, 4H), 1.49-1.34 (m, 3H), 1.21- 1.19 (d,J = 8.0 Hz, 1H), 1.03-1.02 (d, J = 4.0 Hz, 1H), 0.56-0.55 (m, 1H)

(ES, m/z): 363 [M + H]⁺ 11.15 (br, 1H), 7.39-7.16 (m, 3H), 4.92-4.86 (m,1.5H), 4.72-4.67 (m, 0.6H), 4.48-4.44 (m, 1H), 4.29-4.14 (m, 2H),3.65-3.64 (m, 1H), 3.51-3.48 (m, 1H), 2.98-2.79 (m, 1H), 1.67-1.39 (m,2H), 1.20-1.18 (m, 2H), 1.17-1.01 (m, 6H), 0.98-0.95 (m, 1H), 0.88-0.83(m, 2H)

(ES, m/z): 349 [M + H]⁺ 11.12 (br, 1H), 7.35-7.15 (m, 3H), 4.95-4.83 (m,2H), 4.61-4.56 (d, J = 8.70 Hz, 1H), 4.47-4.42 (m, 1H), 4.25-4.14 (m,2H), 3.78-3.61 (m, 2H), 3.22-3.07 (m, 2H), 2.34-2.19 (m, 1H), 1.99-1.70(m, 2H), 1.50-1.46 m, 1H), 1.39-1.26 (m, 1H), 1.17-1.09 (m, 2H),1.04-1.1.02 (d, J = 3.30 Hz, 2H), 0.85- 0.80 (m, 1H)

(ES, m/z): 335 [M + H]⁺ 11.20-10.00 (br, 1H), 9.50-8.45 (br, 1H),7.34-7.19 (m, 3H), 4.93-4.77 (m, 2H), 4.69-4.67 (m, 1H), 4.48-4.08 (m,5H), 3.81-3.31 (m, 1H), 2.01-1.88 (m, 2H), 1.20-1.02 (m, 3H), 0.77-0.66(m, 3H)

(ES, m/z): 389 [M +H]⁺ 11.25 (s, 1H), 9.08 (s, 1H), 7.35-7.20 (m, 3H),7.18-7.02 (m, 2H), 6.92-6.79 (m, 2H), 4.99-4.85 (m, 2H), 4.67-4.61 (d, J= 17.7 Hz, 1H), 4.54-4.48 (d, J = 15.9 Hz, 1H), 4.31-4.05 (m, 4H), 3.08-2.99 (m, 1H), 2.85-2.71 (m, 1H), 2.38- 2.22 (m, 1H), 1.22-11.05 (m, 3H)

(ES, m/z): 335 [M + H]⁺ 11.10 (s, 1H), 9.02 (s, 1H), 7.34-7.27 (m,1.5H), 7.24-7.22 (d, J = 8 Hz, 0.5H), 7.16-7.14 (m, 1H), 4.89-4.78 (m,1.5H), 4.46-4.42 (d, J = 16.4 Hz, 1H), 4.26-4.13 (m, 2.4H), 3.75-3.65(m, 1H), 3.07-3.03 (d, J = 15.2 Hz, 3H), 2.91-2.82 (m, 0.5H), 2.73-2.65( m, 0.6H), 2.40-2.29 (m, 1H) 2.00-1.88 (m, 1.5H), 1.80-1.72 (m, 0.5H),1.68-1.61 (m, 0.6H), 1.15-1.01 (m, 3H)

(ES, m/z): 335 [M + H]⁺ 11.13 (s, 1H), 9.02 (s, 1H), 7.32-7.23 (m, 2H),7.16 (s, 1H), 4.93-4.81 (m, 2H), 4.49-4.13 (m, 3H), 3.80-3.74 (m, 1H),3.27 (s, 0.5H), 3.13-3.04 (m, 3.5H), 2.49-1.76 (m, 4H), 1.15- 1.02 (m,3H)

(ES, m/z): 335 [M + H]⁺ 11.12 (s, 1H), 9.04 (s, 1H), 7.33-7.17 (m, 3H),4.91-4.35 (m, 3H), 4.33-3.95 (m, 3H), 3.75-3.42 (m, 2H), 2.74-2.56 (m,1H), 2.49-2.18 (m, 1H), 2.07-1.64 (m, 3H), 1.47-1.45 (m, 1H), 1.18-1.17(d, J = 8.7 Hz, 1H), 1.05-1.03 (d, J = 6.6 Hz, 2H)

(ES, m/z): 353 [M + H]⁺ 11.12 (br, 1H), 9.00 (br, 1H), 7.30-7.21 (m,2H), 7.15 (s, 1H), 4.90-4.83 (m, 1H), 4.74-4.59 (m, 2H), 4.31-4.18 (m,2H), 3.75-3.42 (m, 4H), 2.18-1.82 (m, 3H), 1.73-1.42 (m, 1H), 1.21-1.05(m, 3H)

(ES, m/z): 349 [M + H]⁺ 11.15 (s, 1H), 9.07 (s, 1H), 7.40-7.22 (m, 2H),7.19-7.15 (t, J = 9.3 Hz, 1H), 4.92- 4.50 (m, 2H), 4.44-4.16 (m, 3H),3.71-3.43 (m, 4H), 2.80-2.75 (d, J = 13.2 Hz, 1H), 1.80-1.61 (m, 4H),1.46-1.22 (m, 2H), 1.20-1.02 (m, 3H)

(ES, m/z): 363 [M + H]⁺ 11.16 (s, 1H), 9.04 (s, 1H), 7.45-7.15 (m, 3H),4.98-4.81 (m, 2H), 4.64-4.52 (m, 1H), 4.30-4.19 (m, 2H), 3.87-3.50 (m,3H), 3.14- 3.03 (m, 0.5H), 2.92-2.86 (m, 0.1H), 2.67- 2.61 (m, 0.4H),2.42-2.32 (m, 0.4H), 2.23- 2.12 (m, 0.3H), 1.90-1.83 (m, 0.2H), 1.79-1.52 (m, 1.2H), 1.47-1.38 (m, 0.3H), 1.25- 1.18 (m, 1.8H), 1.05-1.02 (t,J = 7.4 Hz, 2H), 0.91-0.88 (t, J = 5.6 Hz, 1.6H), 0.82- 0.78 (m, 2H),0.65-0.63 (d, J = 6.8 Hz, 0.6H), 0.51-0.49 (d, J = 6.8 Hz, 1H), 0.25-0.23 (d, J = 8 Hz, 1H)

(ES, m/z): 349 [M + H]⁺ 7.33-7.24 (m, 3H), 5.00-4.92 (m, 2H), 4.86-4.68(m, 2H), 4.62-4.48 (m, 1H), 4.29-4.22 (m, 2H), 2.29-1.71 (m, 4H), 1.37-1.26 (m, 4.7H), 1.23 (s, 0.5H), 1.19- 1.12 (m, 3H), 0.89 (s, 1H)

(ES, m/z): 335 [M + H]⁺ 11.14 (s, 1H), 9.00 (s, 1H), 7.31-7.23 (m, 3H),5.59-5.54 (d, J = 20.0 Hz, 0.3H), 5.09- 4.85 (m, 0.7H), 4.84-4.74 (m,0.8H), 4.72- 4.68 (m, 0.7H), 4.53-4.43 (m, 0.5H), 4.30- 4.10 (m, 2H),3.93-3.76 (m, 1H), 3.74-3.56 (m, 0.8H), 3.45-3.35 (m, 0.2H), 2.60-2.50(m, 1H), 1.89-1.75 (m, 1H), 1.72-1.60 (m, 0.5H), 1.57-1.46 (m, 0.5H),1.44-1.30 (m, 2.5H), 1.29-1.18 (m, 1.5H), 1.15-0.97 (m, 3H)

(ES, m/z): 349 [M + H]⁺ 11.15 (s, 1H), 9.05 (s, 1H), 7.35-7.22 (m, 3H),4.84-4.09 (m, 5H), 3.63-3.34 (m, 2H), 3.21-3.14 (m, 3H), 2.42-1.78 (m,5H), 1.53- 1.50 (m, 1H), 1.25-0.99 (m, 3H)

(ES, m/z): 379 [M + H]⁺ 11.10 (s, 1H), 9.00 (s, 1H), 7.28-7.25 (m, 2H),7.18-7.15 (m, 1H), 4.89-4.44 (m, 3H), 4.28- 4.17 (m, 2H), 3.74-3.60 (m,4H), 3.58-3.52 (m, 1H), 3.28-3.24 (m, 2H), 2.80-2.10 (m, 2H), 1.72-1.68(m, 2H), 1.31-1.26 (m, 2H), 1.23- 1.02 (m, 3H)

(ES, m/z): 335 [M + H]⁺ 11.13 (s, 1H), 9.01 (s, 1H), 7.33-7.19 (d, J =52.8 Hz, 3H), 5.02-4.39 (m, 3H), 4.19 (s, 2H), 3.60-3.49 (d, J = 44 Hz,1H), 3.18-3.01 (d, J = 68 Hz, 4H), 1.27-1.02 (m, 3H), 0.93-0.61 (m, 4H)

(ES, m/z): 349 [M + H]⁺ 11.16 (s, 1H), 7.37-7.16 (m, 3H), 5.83 (br, 1H),4.95-4.78 (m, 2H), 4.71-4.39 (m, 1H), 4.28-4.17 (m, 2H), 3.97-3.75 (m,1H), 3.62- 3.56 (m, 1H), 3.34-3.31 (m, 1H), 2.75-2.51 (m, 1H), 1.74-1.55(m, 3H), 1.21-1.01 (m, 5H), 0.79-0.77 (d, J = 6.6 Hz, 1H), 0.56-0.54 (d,J = 6.6 Hz, 1H)

(ES, m/z): 377 [M + H]⁺ 10.70 (s, 1H), 9.03 (s, 1H), 7.31-7.16 (m 3H),4.96-4.32 (m, 3H), 4.28-4.14 (m 2H), 4.06- 3.90 (m, 2H), 3.82-3.68 (m,2H), 2.90-2.12 (m, 2H), 1.19-1.03 (m, 3H)

(ES, m/z): 377 [M + H]⁺ 10.97 (s, 0.3H), 9.02 (s, 0.4H), 7.34-7.16 (m,3H), 4.91-4.69 (m, 2H), 4.68-4.35 (m, 1H), 4.27-4.20 (m, 2H), 4.00-3.40(m, 2H), 3.28-2.96 (m, 1H), 2.94-2.69 (m, 1H), 1.82- 1.42 (m, 3H),1.40-1.18 (m, 2H), 1.17-1.02 (m, 2H), 0.87-0.78 (m, 4H), 0.77-0.64 (m,2H), 0.55-0.35 (m, 1H)

(ES, m/z): 411 [M + H]⁺ 10.88 (s, 1H), 9.01 (s, 1H), 7.37-7.23 (m, 7H),7.17 (m, 1H), 4.91-4.78 (m, 1H), 4.48-4.39 (m, 1H), 4.34-4.30 (m, 2H),4.25- 4.17 (m, 2H), 3.99-3.86 (m, 1H), 3.15-2.79 (m, 1H), 2.38-2.31 (m,1H), 2.27-2.09 (m, 2H), 1.98-1.70 (m, 2H), 1.16-1.14 (d, J = 6.0 Hz,1H), 1.04-1.02 (d, J = 6.3 Hz, 2H) cis/trans (ES, m/z): 417 [M + H]⁺7.39-7.26 (m, 3H), 5.06-4.92 (m, 2H), 4.76-4.59 (m, 1H), 4.56-4.50 (m,2H), 2.78-2.22 (m, 2H), 2.18-1.43 (m, 5H), 1.37-1.32 (m, 2H), 1.19-0.99(m, 2H)

(ES, m/z): 417 [M + H]⁺ 7.38-7.26 (m, 3H), 5.03-4.92 (m, 2H), 4.75-4.69(m, 1H), 4.56-4.50 (m, 1H), 4.29-4.19 (m, 3H), 2.78-2.54 (m, 1H),2.18-2.05 (m, 1H), 1.94-1.82 (m, 2H), 1.70- 1.59 (m, 2H), 1.38-1.31 (m,2H), 1.18-1.16 (m, 2H)

(ES, m/z): 349 [M + H]⁺ 11.09 (br s, 1H), 9.02 (br s, 1H), 7.32- 7.16(m, 3H), 5.18-5.12 (d, J = 16.8 Hz, 1H), 4.78-4.50 (m, 2H), 4.25-4.09(m, 2H), 3.45-3.43 (m, 1H), 2.73-2.15 (m, 2H), 1.55-1.44 (m, 2H),1.37-1.33 (m, 4H), 1.27-1.22 (m, 2H), 1.20-1.12 (m, 2H), 1.12-1.09 (m,2H)

(ES, m/z): 349 [M + H]⁺ 11.14-11.10 (br s, 1H), 9.03-9.01 (br s, 1H),7.32-7.14 (m, 3H), 5.75-5.69 (d, J = 17.4 Hz, 1H), 4.98-4.88 (m, 2H),4.32-4.15 (m, 2H), 3.87-3.65 (m, 1H), 3.24-3.17 (m, 1H), 2.27- 2.07 (m,1H), 1.58-1.48 (m, 3H), 1.35 (s, 2H), 1.25-1.23 (d, J = 6.6 Hz, 1H),1.19-1.17 (d, J = 6.6 Hz, 1H), 1.17-1.09 (m, 2H), 0.95 (s, 2H)

(ES, m/z): 397 [M + H]⁺ 11.16 (s, 1H), 9.02 (s, 1H), 7.40-7.16 (m, 5H),6.93-6.77 (m, 3H), 4.92-4.86 (d, 1H), 4.86-4.19 (m, 5H), 3.11-1.9 (m,5H), 1.19- 1.03 (m, 3H)

(ES, m/z): 397 [M + H]⁺ 11.12 (s, 1H), 9.00 (s, 1H), 7.36-7.21 (m, 4H),7.17 (s, 1H), 6.91-6.87 (t, J = 7.2 Hz, 1H), 6.76-6.72 (t, J = 8.6 Hz,2H), 4.94- 4.85 (m, 1.5H), 4.64-4.61 (m, 1H), 4.50-4.36 (m, 1H),4.26-4.17 (m, 2H), 3.28-2.00 (m, 5H), 1.15-1.04 (m, 3H)

(ES, m/z): 367 [M + H]⁺ 13.13 (br s, 3H), 8.37 (br s, 2H), 7.24- 7.45(m, 7H), 7.16-7.24 (m, 2H), 6.51 (br d, J = 16.7 Hz, 2H), 5.69 (br dd, J= 10.0, 5.3 Hz, 2H), 4.92-5.29 (m, 4H), 4.66- 4.92 (m, 2H), 4.18-4.53(m, 4H), 4.08 (q, J = 7.0 Hz, 2H), 1.41 (d, J = 6.4 Hz, 3H), 1.10-1.35(m, 4H)

Example 37—Preparation of(S)—N-hydroxy-3-methyl-4-((R)-tetrahydro-2H-pyran-3-carbonyl)-2,3,4,5-tetrahydrobenzo[f][1,4]oxazepine-8-carboxamideand(S)—N-hydroxy-3-methyl-4-((S)-tetrahydro-2H-pyran-3-carbonyl)-2,3,4,5-tetrahydrobenzo[f][1,4]oxazepine-8-carboxamide

Step-1: Methyl(S)-3-methyl-4-((R)-tetrahydro-2H-pyran-3-carbonyl)-2,3,4,5-tetrahydrobenzo[f][1,4]oxazepine-8-carboxylateand Methyl(S)-3-methyl-4-((S)-tetrahydro-2H-pyran-3-carbonyl)-2,3,4,5-tetrahydrobenzo[f][1,4]oxazepine-8-carboxylate

Into a 8-mL vial, were placed a solution oftetrahydro-2H-pyran-3-carboxylic acid (106 mg, 0.81 mmol, 1 equiv) inDMF (3 mL), HATU (371 mg, 0.98 mmol, 1.2 equiv), methyl(S)-3-methyl-2,3,4,5-tetrahydrobenzo[f][1,4]oxazepine-8-carboxylate (180mg, 0.81 mmol, 1 equiv), and DIEA (315 mg, 2.44 mmol, 3 equiv). Theresulting solution was stirred overnight at room temperature. Thereaction was then quenched by the addition of H₂O (5 mL) and extractedwith EtOAc (3×10 mL). The combined organic layers was washed with H₂O(2×10 mL), dried over anhydrous Na₂SO₄, filtered, and concentrated undervacuum. The residue was purified by silica gel chromatography(EtOAc/pet. ether, 1:1). The product mixture was separated byChiral-Prep-HPLC (Column Chiralpak IB, 5 μm, 2×25 cm; Mobile Phase A:hexanes; Mobile Phase B: EtOH; Gradient: 40% B for 22 min; Detector, UV254, 220 nm) to afford the title compounds as off-white solids (firsteluting isomer: 60 mg, 22% yield; second eluting isomer: 86 mg, 32%yield). MS: (ES, m/z): 334 [M+H]⁺.

Step-2:(S)—N-Hydroxy-3-methyl-4-((R)-tetrahydro-2H-pyran-3-carbonyl)-2,3,4,5-tetrahydrobenzo[f][1,4]oxazepine-8-carboxamideand(S)—N-Hydroxy-3-methyl-4-((S)-tetrahydro-2H-pyran-3-carbonyl)-2,3,4,5-tetrahydrobenzo[f][1,4]oxazepine-8-carboxamide

Into 8-mL vials, was placed each of the separated isomers from Step 1(60 mg, 0.18 mmol; and 86 mg, 0.26 mmol; 1 equiv) in THF/MeOH (4; 1, 2mL). Then aq. 1N NaOH (2 equiv) and NH₂OH (50% in H₂O, 30 equiv) wereadded simultaneously. The resulting solution was stirred for 2 h at roomtemperature. The crude products were purified by Prep-HPLC (Column:Xbridge RP C18 OBD, 5 μm, 19×150 mm; Mobile Phase A: Water/0.05% formicacid; Mobile Phase B: MeCN; Flow rate: 25 mL/min; Gradient: 5% B to 40%B in 7 min; Detector, UV 254, 220 nm) to afford the title compounds asoff-white solids. The product from the reaction with the first elutingisomer from Step 1: (30.3 mg, 50% yield). ¹H-NMR (400 MHz, DMSO-d₆)δ(ppm): 11.16 (br s, 1H), 7.50-7.10 (m, 3H), 4.96-4.72 (m, 2H),4.56-4.41 (m, 1H), 4.32-4.15 (m, 2H), 3.92-3.75 (m, 2H), 3.37-3.31 (m,1H), 3.27-3.16 (m, 1H), 2.95-2.75 (m, 1H), 1.90-1.52 (m, 2H), 1.42-1.32(m, 2H), 1.25-1.18 (m, 1H), 1.13-0.95 (m, 2H). MS: (ES, m/z): 335[M+H]⁺. The product from the reaction with the second eluting isomerfrom Step 1: (31.3 mg, 36% yield). ¹H-NMR (400 MHz, DMSO-d₆) δ(ppm):11.17 (br s, 1H), 7.46-7.13 (m, 3H), 4.96-4.84 (m, 1H), 4.85-4.76 (m,0.5H), 4.71-4.65 (m, 0.5H), 4.51-4.44 (m, 1H), 4.33-4.15 (m, 2H),3.85-3.71 (m, 1.5H), 3.42-3.35 (m, 0.5H), 3.30-3.07 (m, 2H), 2.87-2.65(m, 1H), 1.97-1.76 (m, 1H), 1.70-1.34 (m, 3H), 1.20 (d, J=6.4 Hz, 1.4H),1.03 (d, J=6.4 Hz, 1.6H). MS: (ES, m/z): 335 [M+H]⁺.

TABLE 20 The following compounds were prepared according to the methodof Example 37, with these modifications: (1) In Step 1, the reactionsolvent can be DMF or CH₂C1₂; (2) In Step 1, the chiral separation canbe performed by Prep-HPLC using the Chiralpak IB, 5 μm, 2 × 25 cm columnor the Chiralpak IC, 5 μm, 2 × 25 cm column; by Prep-SFC using theChiralpak AS-H, 5 μm, 5 × 25 cm column; Mobile Phase: 50% CO₂, 50% MeOH;Detector, UV 220 nm; or by silica gel prep-TLC (EtOAc/pet. ether, 1:1);(3) In Step 2, the Prep-HPLC column can be XBridge RP C18 OBD, 5 μm, 19× 150 mm using formic acid as the additive to the water Mobile Phase A;or the column Sunfire C18, 5 μm, 19 × 150 mm using NH₄HCO₃ as theadditive to the water Mobile Phase A. Found Structure M + H ¹H-NMR (400MHz, DMSO-d₆) δ (ppm)

(ES, m/z): 363 [M + H]⁺ 11.14 (br s, 1H), 9.02 (br s, 1H), 7.47-7.11 (m,3H), 4.94-4.62 (m, 2H), 4.50-4.37 (m, 1H), 4.33-4.10 (m, 2H), 3.22-3.19(d, 3H), 3.09-2.94 (m, 1H), 2.42-2.39 (m, 1H), 2.06-1.92 (m, 1H),1.84-1.60 (m, 2H), 1.55- 1.30 (m, 1H), 1.30-1.07 (m, 4H), 1.06-0.81 (m,3H)

(ES, m/z): 363 [M + H]⁺ 11.13 (br, 1H), 9.02 (br s, 1H), 7.45-7.12 (m,3H), 4.95-4.61 (m, 2H), 4.51-4.38 (m, 1H), 4.35-4.11 (m, 2H), 3.45-3.35(m, 1H), 3.16-3.15 (d, 3H), 2.65-2.55 (m, 1H), 1.92-1.55 (m, 3H),1.53-1.25 (m, 4H), 1.19 (m, 1.5 H), 1.18-1.10 (m, 0.5H), 1.03 (m, 1.5H),0.75-0.62 (m, 0.5H)

(ES, m/z): 321 [M + H]⁺ 11.18 (br s, 1H), 7.49-7.14 (m, 3H), 4.95-4.82(m, 1.5H), 4.74-4.41 (m, 1.5H), 4.35-4.13 (m, 2H), 4.06- 3.89 (m, 1H),3.78-3.18 (m, 4H), 2.12-1.90 (m, 1H), 1.67-1.45 (m, 1H), 1.20-1.04 (m,3H)

(ES, m/z): 321 [M + H]⁺ 11.12 (br s, 1H), 9.01 (br s, 1H), 7.38-7.22 (m,2H), 7.16-7.15 (m, 1H), 4.92-4.71 (m, 1.5H), 4.66-4.50 (m, 0.5H),4.50-4.46 (m, 1H), 4.26-4.18 (m, 2H), 3.84-3.82 (m, 0.5H), 3.74-3.73 (m,0.5H), 3.65-3.60 (m, 2H), 3.34-3.31 (m, 1H), 3.20-3.19 (m, 1H),2.17-2.06 (m, 1H), 2.00-1.95 (m, 0.5H), 1.75-1.70 (m, 0.5H), 1.17- 1.02(m, 3H)

(ES, m/z): 347 [M + H]⁺ 10.90 (br s, 1H), 9.10 (br s, 1H), 7.36-7.16 (m,3H), 4.91-4.17 (m, 7H), 2.85-2.82 (m, 1H), 1.70-1.39 (m, 6H), 1.22-1.04(m, 3H)

(ES, m/z): 347 [M + H]⁺ 11.15 (br s, 1H), 9.00 (br s, 1H), 7.48-7.17 (m,3H), 4.96-4.90 (m, 2H), 4.72-4.66 (m, 2H), 4.51-4.16 (m, 2H), 3.84-2.70(m, 2H), 2.00-1.79 (m, 1H), 1.52-1.03 (m, 8H)

(ES, m/z): 363 [M + H]⁺ 11.11 (br s, 1H), 9.05 (br s, 1H), 7.40-7.25 (m,2H), 7.18-7.15 (m, 1H), 4.92-4.49 (m, 3H), 4.32-4.15 (m, 2H), 3.64-3.56(m, 2H), 3.02-2.99 (m, 1H), 1.49-1.42 (m, 2H), 1.32-1.78 (m, 3.5H),1.12-1.03 (m, 4H), 0.96 (s, 2H), 0.88 (s, 0.5H)

(ES, m/z): 363 [M + H]⁺ 11.09 (br s, 1H), 9.06 (br s, 1H), 7.34 (s, 1H),7.31- 7.19 (m, 1H), 7.16-1.15 (d, J = 1.5 Hz, 1H), 4.94- 4.58 (m, 2H),4.50-4.16 (m, 3H), 3.63-3.62 (m, 1H), 3.42-3.41 (m, 1H), 3.13-2.73 (m,1H), 1.59- 1.45 (m, 1H), 1.29-1.23 (m, 1.5H), 1.21-1.17 (m, 5H), 1.13(s, 2H), 1.04-0.82 (m, 3H), 0.86-0.82 (m, 0.5H)

(ES, m/z): 335 [M + H]⁺ 11.15 (br s, 1H), 9.02 (br s, 1H), 7.18-7.33 (m,3H), 4.93-3.78 (m, 7H), 3.52-3.45 (m, 1H), 1.74-1.38 (m, 5.5H),1.38-1.02 (m, 3.5H)

(ES, m/z): 335 [M + H]⁺ 11.15 (br s, 1H), 9.02 (br s, 1H), 7.18-7.33 (m,3H), 4.93-4.12 (m, 6H), 3.82-3.78 (m, 0.5H), 3.52-3.24 (m, 1.5H),1.74-1.20 (m, 6H), 1.20-1.02 (m, 3H)

(ES, m/z): 335 [M + H]⁺ 11.07-11.12 (br s, 1H), 9.02 (br s, 1H),7.42-7.18 (m, 3H), 4.94-4.43 (m, 3H), 4.24-4.15 (m, 2H), 4.12-3.67 (m,4H), 2.28-2.21 (m, 1H), 1.95-1.80 (m, 1H), 1.28- 1.17 (m, 6H)

(ES, m/z): 335 [M + H]⁺ 11.09 (br s, 1H), 9.00 (br s, 1H), 7.16-7.40 (m,3H), 4.90-4.43 (m, 3H), 4.21-4.12 (m, 2H), 3.79-3.72 (m, 2H), 3.57-3.48(m, 2H), 2.48-2.26 (m, 0.5H), 1.86-1.84 (m, 1H), 1.83-1.60 (m, 0.5H),0.89-1.32 (m, 6H)

Example 38—Preparation of(S)-4-(1-acetylpiperidine-4-carbonyl)-N-hydroxy-3-methyl-2,3,4,5-tetrahydrobenzo[f][1,4]oxazepine-8-carboxamide

Step-1: Methyl(S)-4-(1-(tert-butoxycarbonyl)piperidine-4-carbonyl)-3-methyl-2,3,4,5-tetrahydrobenzo[f][1,4]oxazepine-8-carboxylate

Into a 8-mL vial, was placed1-(tert-butoxycarbonyl)piperidine-4-carboxylic acid (311 mg, 1.36 mmol,1.2 equiv). Then HATU (516 mg, 1.36 mmol, 1.2 equiv), methyl(S)-3-methyl-2,3,4,5-tetrahydrobenzo[f][1,4]oxazepine-8-carboxylate (250mg, 1.13 mmol, 1 equiv) in DMF (0.5 mL) and DIEA (438 mg, 3.39 mmol, 3equiv) were added with stirring at 0° C. The resulting solution wasstirred for 18 h at room temperature. The reaction was diluted with H₂O(30 mL) and extracted with EtOAc (3×30 mL). The combined organic layerswere washed sequentially with H₂O (3×20 mL) and brine (2×20 mL), driedover anhydrous Na₂SO₄, filtered, and concentrated under vacuum to affordthe title compound as a brown solid (400 mg, 82% yield). MS: (ES, m/z):433 [M+H]⁺.

Step-2: Methyl(S)-3-methyl-4-(piperidine-4-carbonyl)-2,3,4,5-tetrahydrobenzo[f][1,4]oxazepine-8-carboxylate

Into a 8-mL vial, was placed methyl(S)-4-(1-(tert-butoxycarbonyl)piperidine-4-carbonyl)-3-methyl-2,3,4,5-tetrahydrobenzo[f][1,4]oxazepine-8-carboxylate(400 mg, 0.92 mmol, 1 equiv) in CH₂Cl₂ (1.5 mL). This was followed bythe addition of TFA (1.5 mL) dropwise with stirring at 0° C. Theresulting solution was stirred for 5 h at room temperature, thenconcentrated under vacuum. The residue was dissolved in H₂O (30 mL) andthe pH was adjusted to 9 with aq. 1N NaOH. The resulting solution wasextracted with EtOAc (3×30 mL). The combined organic layers were washedsequentially with H₂O (2×20 mL) and brine (2×20 mL), dried overanhydrous Na₂SO₄, filtered, and concentrated under vacuum to afford thetitle compound as a brown oil (290 mg, 94% yield). MS: (ES, m/z): 333[M+H]⁺.

Step-3: Methyl(S)-4-(1-acetylpiperidine-4-carbonyl)-3-methyl-2,3,4,5-tetrahydrobenzo[f][1,4]oxazepine-8-carboxylate

Into a 8-mL vial, was placed a solution of methyl(S)-3-methyl-4-(piperidine-4-carbonyl)-2,3,4,5-tetrahydrobenzo[f][1,4]oxazepine-8-carboxylate(100 mg, 0.30 mmol, 1 equiv) in CH₂Cl₂ (2 mL). To this was added Et₃N(121 mg, 1.20 mmol, 4 equiv) and a solution of acetyl chloride (26 mg,0.33 mmol, 1.1 equiv) in CH₂Cl₂ (0.5 mL) dropwise with stirring at 0° C.The resulting solution was stirred for 18 h at room temperature, thenconcentrated under vacuum. The residue was dissolved in CH₂Cl₂ (30 mL)and washed with H₂O (3×30 mL). The organic phase was dried overanhydrous MgSO₄, filtered, and concentrated under vacuum to afford thetitle compound as a brown solid (100 mg, 89% yield). MS: (ES, m/z): 375[M+H]⁺.

Step-4:(S)-4-(1-Acetylpiperidine-4-carbonyl)-N-hydroxy-3-methyl-2,3,4,5-tetrahydrobenzo[f][1,4]oxazepine-8-carboxamide

Into a 8-mL vial, was placed a solution of methyl(S)-4-(1-acetylpiperidine-4-carbonyl)-3-methyl-2,3,4,5-tetrahydrobenzo[f][1,4]oxazepine-8-carboxylate(100 mg, 0.27 mmol, 1 equiv) in THF/MeOH (4:1, 2 mL), then aq. 1N NaOH(0.53 mL, 2 equiv) and aq. NH₂OH (50% in H₂O, 0.53 mL, 30 equiv) wereadded simultaneously. The resulting solution was stirred for 3 h at roomtemperature. The crude product was purified by Prep-HPLC (Column:Sunfire C18, 5 μm, 19×150 mm; Mobile Phase A: Water/0.05% TFA; MobilePhase B: MeCN; Flow rate: 25 mL/min; Gradient: 5% B to 40% B in 8 min;Detector, UV 254, 220 nm) to afford the title compound as an off-whitesolid (36.7 mg, 28% yield). ¹H-NMR (400 MHz, DMSO-d₆) δ(ppm): 11.15 (brs, 1H), 9.18-8.62 (m, 1H), 7.44-7.16 (m, 3H), 4.92-4.76 (m, 2H),4.49-4.45 (m, 1H), 4.34-4.14 (m, 3H), 3.82-3.61 (m, 1H), 3.11-3.09 (m,1H), 2.88-2.79 (m, 1H), 2.60-2.57 (m, 1H), 1.97-1.91 (m, 3H), 1.64-1.56(m, 2H), 1.40-1.29 (m, 1H), 1.24-1.03 (m, 3H), 0.92 (m, 1H). MS: (ES,m/z): 376 [M+H]⁺.

TABLE 21 The following compounds were prepared according to the methodof Example 38. Found Structure M + H ¹H-NMR (400 MHz, DMSO-d₆) δ (ppm)

(ES, m/z): 362 [M + H]⁺ 11.16 (br s, 1H), 9.32-8.55 (br s, 1H),7.41-7.17 (m, 3H), 4.92-4.73 (m, 2H), 4.53-4.49 (m, 1H), 4.24-4.20 (m,2H), 3.65-3.53 (m, 1H), 3.52-3.36 (m, 3H), 3.29-3.25 (m, 1H), 2.17-1.98(m, 1H), 1.94-1.92 (m, 1H), 1.89-1.86 (m, 2H), 1.69-1.47 (m, 1H),1.23-1.04 (m, 3H)

Example 39—Preparation of(S)-4-(1-formylpiperidine-4-carbonyl)-N-hydroxy-3-methyl-2,3,4,5-tetrahydrobenzo[f][1,4]oxazepine-8-carboxamide

Step-1: Methyl(S)-4-(1-formylpiperidine-4-carbonyl)-3-methyl-2,3,4,5-tetrahydrobenzo[f][1,4]oxazepine-8-carboxylate

Into a 25-mL round-bottom flask, was placed methyl(S)-3-methyl-4-(piperidine-4-carbonyl)-2,3,4,5-tetrahydrobenzo[f][1,4]oxazepine-8-carboxylate(170 mg, 0.51 mmol, 1 equiv) in ethyl formate (10 mL). The resultingsolution was stirred for 20 h at 60° C. in an oil bath, thenconcentrated under vacuum. The residue was dissolved in EtOAc (20 mL)and washed with H₂O (2×20 mL), dried over anhydrous Na₂SO₄, filtered,and concentrated under vacuum. The residue was purified by silica gelchromatography (MeOH/CH₂Cl₂, 1:20) to afford the title compound as acolorless oil (79 mg, 43% yield). MS: (ES, m/z): 361 [M+H]⁺.

Step-2:(S)-4-(1-Formylpiperidine-4-carbonyl)-N-hydroxy-3-methyl-2,3,4,5-tetrahydrobenzo[f][1,4]oxazepine-8-carboxamide

Into a 8-mL vial, was placed a solution of methyl(S)-4-(1-formylpiperidine-4-carbonyl)-3-methyl-2,3,4,5-tetrahydrobenzo[f][1,4]oxazepine-8-carboxylate(79 mg, 0.22 mmol, 1 equiv) in THF/MeOH (4:1, 2 mL), then aq. NH₂OH (50%in H₂O, 0.43 mL, 30 equiv) and aq. 1N NaOH (0.44 mL, 2 equiv) were addedsimultaneously. The resulting solution was stirred for 2 h at roomtemperature. The crude product was purified by Prep-HPLC (Column:Sunfire C18, 5 μm, 19×150 mm; Mobile Phase A: Water/0.05% formic acid;Mobile Phase B: MeCN; Flow rate: 25 mL/min; Gradient: 5% B to 23% B in 7min; Detector, UV 254, 220 nm) to afford the title compound as a lightpink solid (11.2 mg, 14% yield). ¹H-NMR (400 MHz, DMSO-d₆) δ(ppm): 11.15(br s, 1H), 9.09 (br s, 1H), 7.94-7.88 (m, 1H), 7.44-7.16 (m, 3H),4.93-4.71 (m, 2H), 4.50-4.46 (m, 1H), 4.30-4.14 (m, 3H), 3.75-3.54 (m,1H), 3.13-3.10 (m, 1H), 2.92-2.70 (m, 2H), 1.79-1.61 (m, 2H), 1.45-1.30(m, 1H), 1.27-1.20 (m, 4H). MS: (ES, m/z): 362 [M+H]⁺.

Example 40—Preparation of(S)—N-hydroxy-4-(3-(methoxymethyl)oxetane-3-carbonyl)-3-methyl-2,3,4,5-tetrahydrobenzo[f][1,4]oxazepine-8-carboxamide

Step-1: Methyl(S)-4-(1-(hydroxymethyl)cyclobutane-1-carbonyl)-3-methyl-2,3,4,5-tetrahydrobenzo[f][1,4]oxazepine-8-carboxylate

Into a 10-mL vial, were placed a solution of3-(hydroxymethyl)oxetane-3-carboxylic acid (36 mg, 0.27 mmol, 1 equiv)in DMF (2 mL), HATU (155 mg, 0.41 mmol, 1.50 equiv), methyl(S)-3-methyl-2,3,4,5-tetrahydrobenzo[f][1,4]oxazepine-8-carboxylate (60mg, 0.27 mmol, 1 equiv), and DIEA (175 mg, 1.35 mmol, 5 equiv) at 0° C.The resulting solution was stirred overnight at room temperature. Thereaction was then quenched by the addition of H₂O (5 mL). The resultingsolution was extracted with EtOAc (3×10 mL). The combined organic layerswere washed sequentially with H₂O (10 mL) and brine (10 mL), dried overanhydrous Na₂SO₄, filtered, and concentrated under vacuum. The residuewas purified by silica gel chromatography (EtOAc/pet. ether, 2:1) toafford the title compound as a yellow oil (50 mg, 55% yield). MS: (ES,m/z): 336 [M+H]⁺.

Step-2: Methyl(S)-4-(1-(methoxymethyl)cyclobutane-1-carbonyl)-3-methyl-2,3,4,5-tetrahydrobenzo[f][1,4]oxazepine-8-carboxylate

Into a 10-mL vial, were placed a solution of methyl(S)-4-(1-(hydroxymethyl)cyclobutane-1-carbonyl)-3-methyl-2,3,4,5-tetrahydrobenzo[f][1,4]oxazepine-8-carboxylate(40 mg, 0.12 mmol, 1 equiv) in THE (1 mL). This was followed by theaddition of sodium hydride (60% dispersion in oil, 7 mg, 0.17 mmol, 1.5equiv) in portions at 0° C. To this was added iodomethane (27 mg, 0.19mmol, 1.6 equiv) dropwise with stirring at 0° C. The resulting solutionwas stirred for 30 min at room temperature. The reaction was thenquenched by the addition of NH₄Cl aq. (2 mL). The resulting solution wasextracted with EtOAc (3×10 mL). The combined organic layers were washedsequentially with H₂O (10 mL) and brine (10 mL), dried over anhydrousNa₂SO₄, filtered, and concentrated under vacuum. The residue waspurified by silica gel chromatography (EtOAc/pet. ether, 1:1) to affordthe title compound as a yellow oil (25 mg, 60% yield). MS: (ES, m/z):350 [M+H]⁺.

Step-3:(S)—N-Hydroxy-4-(3-(methoxymethyl)oxetane-3-carbonyl)-3-methyl-2,3,4,5-tetrahydrobenzo[f][1,4]oxazepine-8-carboxamide

Into a 10-mL vial, were placed a solution of methyl(S)-4-(1-(methoxymethyl)cyclobutane-1-carbonyl)-3-methyl-2,3,4,5-tetrahydrobenzo[f][1,4]oxazepine-8-carboxylate(25 mg, 0.07 mmol, 1 equiv) in THF/MeOH (4:1, 2 mL), aq. 1N NaOH (0.14mL, 2 equiv) and NH₂OH (50% in H₂O, 0.14 mL, 30 equiv) were addedsimultaneously. The resulting solution was stirred for 1 h at roomtemperature. The crude product was purified by Prep-HPLC (Column:Sunfire C18, 5 μm, 19×150 mm; Mobile Phase A: Water/0.05% formic acid;Mobile Phase B: MeCN; Flow rate: 25 mL/min; Gradient: 8% B to 60% B in 8min; Detector, UV 254, 220 nm) to afford the title compound as anoff-white solid (7.8 mg, 31% yield). ¹H-NMR (400 MHz, DMSO-d₆) δ(ppm):11.15 (br s, 1H), 9.03 (br s, 1H), 7.36-7.24 (m, 2H), 7.23 (s, 1H), 4.86(d, J=18.0 Hz, 1H), 4.80-4.70 (m, 1H), 4.70-4.59 (m, 1H), 4.49-4.32 (m,3H), 4.29-4.19 (m, 1H), 4.10 (d, J=6.4 Hz, 1H), 3.95-3.71 (m, 2H),3.66-3.48 (m, 1H), 3.26 (s, 1.5H), 3.16 (s, 1H), 1.24 (d, J=6.0 Hz,1.5H), 1.04 (d, J=6.4 Hz, 1.5H). MS: (ES, m/z): 351 [M+H]⁺.

Example 41—Preparation of(S)-4-formyl-N-hydroxy-3-methyl-2,3,4,5-tetrahydrobenzo[f][1,4]oxazepine-8-carboxamide

Step-1: Methyl(S)-4-formyl-3-methyl-2,3,4,5-tetrahydrobenzo[f][1,4]oxazepine-8-carboxylate

Into a 8-mL vial, was placed methyl(S)-3-methyl-2,3,4,5-tetrahydrobenzo[f][1,4]oxazepine-8-carboxylate (100mg, 0.45 mmol, 1 equiv) and ethyl formate (2.5 mL, 1 equiv). Theresulting solution was stirred for 16 h at 57° C. in an oil bath. Theresulting mixture was concentrated under vacuum to afford the titlecompound as a light yellow oil, which was used without purification. MS:(ES, m/z): 250 [M+H]⁺.

Step-2:(S)-4-Formyl-N-hydroxy-3-methyl-2,3,4,5-tetrahydrobenzo[f][1,4]oxazepine-8-carboxamide

Into a 8-mL vial, was placed methyl(S)-4-formyl-3-methyl-2,3,4,5-tetrahydrobenzo[f][1,4]oxazepine-8-carboxylate(100 mg, 0.40 mmol, 1 equiv) in THF/MeOH (4:1, 2.5 mL). To this wasadded aq. 1N NaOH (0.8 mL, 2 equiv) and NH₂OH (50% in H₂O, 0.8 mL, 30equiv). The resulting solution was stirred for 3 h at room temperature.The crude product was purified by Prep-HPLC (Column: Xbridge XP C18, 5μm, 19×150 mm; Mobile Phase A: Water/0.05% TFA; Mobile Phase B: MeCN;Flow rate: 0.7 mL/min; Gradient: 5% B to 46% B in 7 min; Detector, UV254, 220 nm) to afford the title compound as an off-white solid (50.6mg, 35% yield). ¹H-NMR (400 MHz, DMSO-d₆) δ(ppm): 11.15 (br s, 1H), 9.00(br s, 1H), 8.15-8.13 (d, J 7.5 Hz, 1H), 7.35-7.22 (m, 3H), 4.91-4.79(q, 1H), 4.69-4.10 (m, 4H), 1.23-1.09 (m, 3H). MS: (ES, m/z): 251[M+H]⁺.

Example 42—Preparation of(S)-4-acetyl-N-hydroxy-3-methyl-2,3,4,5-tetrahydrobenzo[f][1,4]oxazepine-8-carboxamide

Step-1: Methyl(S)-4-acetyl-3-methyl-2,3,4,5-tetrahydrobenzo[f][1,4]oxazepine-8-carboxylate

Into a 8-mL vial, was placed a solution of methyl(S)-3-methyl-2,3,4,5-tetrahydrobenzo[f][1,4]oxazepine-8-carboxylate (80mg, 0.36 mmol, 1 equiv) in CH₂Cl₂ (2 mL) and Et₃N (110 mg, 1.09 mmol, 3equiv). This was followed by the addition of acetyl chloride (31 mg,0.39 mmol, 1.1 equiv) at 0° C. The resulting solution was stirred for 18h at room temperature and concentrated under vacuum to afford the titlecompound as brown oil (90 mg), which was used without furtherpurification. MS: (ES, m/z): 264 [M+H]⁺.

Step-2:(S)-4-Acetyl-N-hydroxy-3-methyl-2,3,4,5-tetrahydrobenzo[f][1,4]oxazepine-8-carboxamide

Into a 8-mL vial, was placed a solution of methyl(S)-4-acetyl-3-methyl-2,3,4,5-tetrahydrobenzo[f][1,4]oxazepine-8-carboxylate(90 mg, 0.34 mmol, 1 equiv) in THF/MeOH (4:1, 2 mL). Then aq. 1N NaOH(0.68 mL, 2 equiv) and NH₂OH (50% in water, 0.67 mL, 30 equiv) wereadded simultaneously. The resulting solution was stirred for 14 h atroom temperature. The crude product was purified by Prep-HPLC (Column:Sunfire C18, 5 μm, 19×150 mm; Mobile Phase A: Water/0.05% TFA; MobilePhase B: MeCN; Flow rate: 25 mL/min; Gradient: 4% B to 18% B in 6 min;Detector, UV 254, 220 nm) to afford the title compound as an off-whitesolid (12.3 mg, 10% yield). ¹H-NMR (400 MHz, DMSO-d₆) δ(ppm): 11.15 (brs, 1H), 9.00 (br s, 1H), 8.15-8.13 (d, J 7.5 Hz, 1H), 7.35-7.22 (m, 3H),4.91-4.79 (q, 1H), 4.69-4.10 (m, 4H), 1.23-1.09 (m, 3H). MS: (ES, m/z):265 [M+H]⁺.

TABLE 22 The following compounds were prepared according to the methodof Example 42. Found Structure M + H ¹H-NMR (400 MHz, DMSO-d₆) δ (ppm)

(ES, m/z): 305 [M + H]⁺ 11.11 (br s, 1H), 9.00 (br s, 1H), 7.34- 7.25(m, 2H), 7.16 (s, 1H), 4.86-4.79 (m, 2H), 4.46-4.17 (m, 3H), 3.36-3.32(m, 2H), 2.18-1.70 (m, 6H), 1.15-1.01 (m, 3H)

(ES, m/z): 327 [M + H]⁺ 11.17-11.16 (br s, 1H), 9.03 (br s, 1H),7.45-7.22 (m, 7H), 7.05-7.04 (d, J = 3.9 Hz, 1H), 5.02-4.63 (m, 2H),4.31- 4.29 (t, J = 5.4 Hz, 1H), 4.24-4.04 (m, 2H), 1.20-1.18 (d, J = 6.3Hz, 3H)

Example 43—Preparation of(S)—N-hydroxy-4-(4-(methoxymethyl)tetrahydro-2H-pyran-4-carbonyl)-3-methyl-2,3,4,5-tetrahydrobenzo[f][1,4]oxazepine-8-carboxamide

Step-1: Methyl(S)-4-(1-(methoxymethyl)cyclohexane-1-carbonyl)-3-methyl-2,3,4,5-tetrahydrobenzo[f][1,4]oxazepine-8-carboxylate

Into a 25-mL 3-necked round-bottom flask purged and maintained with aninert atmosphere of nitrogen, was placed a solution of4-(methoxymethyl)tetrahydro-2H-pyran-4-carboxylic acid (100 mg, 0.57mmol, 1.3 equiv) in CH₂Cl₂ (5 mL) and cat. DMF (1 drop). This wasfollowed by the addition of oxalyl chloride (110 mg, 0.87 mmol, 1.9equiv) dropwise with stirring at 0° C. The resulting solution wasstirred for 2 h at room temperature and then concentrated under vacuum.The residue was dissolved in CH₂Cl₂ (2 mL) to form Solution A. Intoanother 8-mL vial, were placed a solution of methyl(S)-3-methyl-2,3,4,5-tetrahydrobenzo[f][1,4]oxazepine-8-carboxylate (100mg, 0.45 mmol, 1 equiv) in CH₂Cl₂ (4 mL) and Et₃N (136 mg, 1.34 mmol, 3equiv). This was followed by the dropwise addition of Solution A withstirring at 0° C. The resulting solution was stirred for 14 h at roomtemperature. The resulting mixture was then diluted with CH₂Cl₂ (20 mL)and washed with H₂O (2×15 mL). The organic phase was dried overanhydrous Na₂SO₄ and concentrated under vacuum to afford the titlecompound as light brown oil (160 mg, 94% yield). MS: (ES, m/z): 378[M+H]⁺.

Step-2:(S)—N-Hydroxy-4-(4-(methoxymethyl)tetrahydro-2H-pyran-4-carbonyl)-3-methyl-2,3,4,5-tetrahydrobenzo[f][1,4]oxazepine-8-carboxamide

Into a 8-mL vial, was placed a solution of methyl(S)-4-(1-(methoxymethyl)cyclohexane-1-carbonyl)-3-methyl-2,3,4,5-tetrahydrobenzo[f][1,4]oxazepine-8-carboxylate(100 mg, 0.26 mmol, 1 equiv) in THF/MeOH (4:1, 2.5 mL). Then NH₂OH (50%in H₂O, 0.5 mL, 30 equiv) and aq. 1N NaOH (0.53 mL, 2 equiv) were addedsimultaneously. The resulting solution was stirred for 3 h at roomtemperature. The crude product was purified by Prep-HPLC (Column:Gemini-NX C18 110 Å, AXIA Packed, 5 μm, 21.2×150 mm; Mobile Phase A:Water/0.05% formic acid; Mobile Phase B: MeCN; Flow rate: 20 mL/min;Gradient: 5% B to 52% B in 8 min; Detector, UV 254, 220 nm) to affordthe title compound as an off-white solid (8.8 mg, 9% yield). ¹H-NMR (400MHz, DMSO-d₆) δ(ppm): 11.13 (br s, 1H), 8.98 (br s, 1H), 7.30 (s, 2H),7.16 (s, 1H), 4.89-4.76 (m, 2H), 4.63-4.57 (m, 1H), 4.21-4.09 (m, 2H),3.59-3.44 (m, 4H), 3.42-3.23 (m, 2H), 3.19-3.02 (m, 3H), 2.00-1.96 (m,2H), 1.51-1.45 (m, 2H), 1.08-1.07 (d, J=2.6 Hz, 3H). MS: (ES, m/z): 379[M+H]⁺.

TABLE 23 The following compounds were prepared according to the methodof Example 43, with these modifications: In Step 2, the Prep-HPLC columncan be XBridge RP C18 OBD, 5 μm, 19 × 150 mm or the column Sunfire C18,5 μm, 19 × 150 mm, using formic as the additive to the water MobilePhase A. Found Structure M + H ¹H-NMR (400 MHz, DMSO-d₆) δ(ppm)

(ES, m/z): 387 [M + H]⁺ 11.10 (br, 1H), 8.99 (br, 1H), 7.31-6.98 (m,6.5H), 6.41- 6.39 (d, J = 7.6 Hz, 0.5H), 4.84-4.81 (d, J = 13.7 Hz, 1H),4.46-4.32 (m, 1H), 4.21-3.82 (m, 3H), 1.41-1.37 (d, J = 17.5 Hz, 4H),1.22 (s, 2H), 1.01-0.99 (d, J = 6.4 Hz, 2H), 0.57 (s, 1H)

(ES, m/z): 401 [M + H]⁺ 11.09 (br s, 1H), 9.01 (br s, 1H), 7.32-7.31 (m,2H), 7.20 (s, 1H), 7.11-7.07 (m, 2H), 6.98-6.95 (d, J = 9.7 Hz, 2H),4.86-4.81 (m, 3H), 4.28-4.16 (m, 2H), 2.99-2.96 (d, J = 13.6 Hz, 1H),2.76-2.73 (d, J = 13.6 Hz, 1H), 1.20- 1.07 (m, 9H)

(ES, m/z): 377 [M + H]⁺ 11.12 (br s, 1H), 8.98 (br s, 1H), 7.33-7.15 (m,3H), 4.80-4.76 (m, 3H), 4.23-4.09 (m, 2H), 3.74-3.72 (m, 2H), 3.08-3.02(m, 1H), 2.21-1.71 (m, 1H), 1.50-0.62 (m, 14H)

(ES, m/z): 370 [M + H]⁺ 11.03 (br s, 1H), 8.98 (br s, 1H), 8.46-8.29 (m,2H), 7.42-7.04 (m, 4.5H), 6.31-6.30 (d, J = 5.2 Hz, 0.5H), 4.85-4.81 (m,1H), 4.51-4.33 (m, 1H), 4.21-4.18 (m, 0.5H), 4.05-3.82 (m, 2.5H),1.49-1.22 (m, 6H), 1.08-1.01 (m, 2H), 0.52 (s, 1H)

Example 44—Preparation of(R)—N-hydroxy-4-(tetrahydro-2H-pyran-4-carbonyl)-3-(trifluoromethyl)-2,3,4,5-tetrahydrobenzo[f][1,4]oxazepine-8-carboxamide

Step-1: Methyl(R)-3-bromo-4-(((1,1,1-trifluoro-3-hydroxypropan-2-yl)amino)methyl)benzoate

Into a 50-mL round-bottom flask, were placed a solution of methyl3-bromo-4-(bromomethyl)benzoate (1.13 g, 3.67 mmol, 1 equiv) in MeCN/H₂O(1:1, 10 mL) and (2R)-2-amino-3,3,3-trifluoropropan-1-ol hydrochloride(600 mg, 3.62 mmol, 1 equiv). This was followed by the addition of asolution of K₂CO₃ (1.5 g, 10.87 mmol, 3 equiv) in H₂O (4 mL) dropwisewith stirring at room temperature. The resulting solution was stirredfor 72 h at room temperature and then concentrated under vacuum. Theresidue was purified by prep-TLC (EtOAc/pet. ether, 1:3) to afford thetitle compound as an off-white solid (200 mg). MS: (ES, m/z): 356[M+H]⁺.

Step-2: Methyl(R)-3-(trifluoromethyl)-2,3,4,5-tetrahydrobenzo[f][1,4]oxazepine-8-carboxylate

Into a 25-mL sealed tube purged and maintained with an inert atmosphereof nitrogen, were placed a solution of methyl(R)-3-bromo-4-(((1,1,1-trifluoro-3-hydroxypropan-2-yl)amino)methyl)benzoate(200 mg, 0.56 mmol, 1 equiv) in isopropanol (10 mL), K₂CO₃ (117 mg, 0.85mmol, 1.5 equiv) and CuI (43 mg, 0.23 mmol, 0.4 equiv). The resultingsolution was stirred for 19 h at 110° C. in an oil bath. The resultingmixture was concentrated under vacuum. The residue was diluted with H₂O(20 mL) and was extracted with CH₂Cl₂ (3×20 mL). The organic phase waswashed with H₂O (2×20 mL) and concentrated under vacuum. The crudeproduct was purified by silica gel chromatography (EtOAc/pet. ether,3:10) to afford the title compound as a green oil (170 mg). MS: (ES,m/z): 276 [M+H]⁺.

Step-3: Methyl(R)-4-(tetrahydro-2H-pyran-4-carbonyl)-3-(trifluoromethyl)-2,3,4,5-tetrahydrobenzo[f][1,4]oxazepine-8-carboxylate

Into a 8-mL vial, were placed methyl(R)-3-(trifluoromethyl)-2,3,4,5-tetrahydrobenzo[f][1,4]oxazepine-8-carboxylate(25 mg, 0.09 mmol, 1 equiv), CH₂Cl₂ (1.5 mL), Et₃N (28 mg, 0.28 mmol, 3equiv) and tetrahydro-2H-pyran-4-carbonyl chloride (16 mg, 0.11 mmol,1.2 equiv). The resulting solution was stirred for 16 h at roomtemperature. The crude product was purified by Prep-TLC (EtOAc/pet.ether, 1:1) to afford the title compound as yellow oil (35 mg, 99%yield). MS: (ES, m/z): 388 [M+H]⁺.

Step-4:(R)—N-Hydroxy-4-(tetrahydro-2H-pyran-4-carbonyl)-3-(trifluoromethyl)-2,3,4,5-tetrahydrobenzo[f][1,4]oxazepine-8-carboxamide

Into a 8-mL vial, were placed methyl(R)-4-(tetrahydro-2H-pyran-4-carbonyl)-3-(trifluoromethyl)-2,3,4,5-tetrahydrobenzo[f][1,4]oxazepine-8-carboxylate(35 mg, 0.09 mmol, 1 equiv) and THF/MeOH (4:1, 1.5 mL). Then NH₂OH (50%in water, 0.18 mL, 30 equiv) and aq. 1N NaOH (0.18 mL, 2 equiv) wereadded at the same time. The resulting solution was stirred for 2 h atroom temperature. The crude product was purified by Prep-HPLC (Column:Xbridge C18, 5 μm, 19×150 mm; Mobile Phase A: Water/0.05% formic acid;Mobile Phase B: MeCN; Flow rate: 25 mL/min; Gradient: 5% B to 45% B in 7min; Detector, UV 254, 220 nm) to afford the title compound as anoff-white solid (15.4 mg, 44% yield). ¹H-NMR (400 MHz, DMSO-d₆) δ(ppm):11.15 (br s, 1H), 9.06 (br s, 1H), 7.49-7.23 (m, 3H), 5.70-5.50 (m, 1H),5.11-5.04 (m, 1.7H), 4.88-4.76 (m, 1H), 4.60-4.53 (m, 1.3H), 3.90-3.61(m, 2H), 3.48-3.39 (m, 1.3H), 3.16-3.05 (m, 0.7H), 2.99-2.90 (m, 1H),1.75-1.48 (m, 2H), 1.37-1.20 (m, 2H). MS: (ES, m/z): 389 [M+H]⁺.

Example 45—Preparation of(R)—N-hydroxy-4-(oxetane-3-carbonyl)-3-(trifluoromethyl)-2,3,4,5-tetrahydrobenzo[f][1,4]oxazepine-8-carboxamide

Step-1: Methyl(R)-4-(oxetane-3-carbonyl)-3-(trifluoromethyl)-2,3,4,5-tetrahydrobenzo[f][1,4]oxazepine-8-carboxylate

Into a 10-mL vial (vial A) purged and maintained with an inertatmosphere of nitrogen, were placed a solution of cyclobutanecarboxylicacid (25 mg, 0.25 mmol, 1 equiv) in CH₂Cl₂ (5 mL), then oxalyl chloride(13.1 mg, 0.5 equiv) was added at 0° C. and stirred at room temperaturefor 2 h. In vial B was added methyl(R)-3-(trifluoromethyl)-2,3,4,5-tetrahydrobenzo[f][1,4]oxazepine-8-carboxylate(30 mg, 0.11 mmol, 1 equiv) and Et₃N (50 mg, 0.49 mmol, 6 equiv), thenthe solution of vial A was transferred to vial B dropwise. The resultingsolution was stirred for 2 h at room temperature, then concentratedunder vacuum. The residue was purified by silica gel chromatography(EtOAc/pet. ether, 1:1) to afford the title compound as a yellow oil (25mg, 28% yield). MS: (ES, m/z): 360 [M+H]⁺.

Step-2:(R)—N-Hydroxy-4-(oxetane-3-carbonyl)-3-(trifluoromethyl)-2,3,4,5-tetrahydrobenzo[f][1,4]oxazepine-8-carboxamide

Into a 10-mL vial, were placed methyl(R)-4-(oxetane-3-carbonyl)-3-(trifluoromethyl)-2,3,4,5-tetrahydrobenzo[f][1,4]oxazepine-8-carboxylate(35 mg, 0.09 mmol, 1 equiv) and THF/MeOH (4:1, 3 mL). Then NH₂OH (50% inwater, 0.14 mL, 30 equiv) and aq. 1N NaOH (0.14 mL, 2 equiv) were addedat the same time. The resulting solution was stirred for 2 h at roomtemperature. The crude product was purified by Prep-HPLC (Column:Sunfire Prep C18 OBD, 5 μm, 19×150 mm; Mobile Phase A: Water/0.05%formic acid; Mobile Phase B: MeCN; Flow rate: 20 mL/min; Gradient: 5% Bto 68% B in 10 min; Detector, UV 254, 220 nm) to afford the titlecompound as a brown oil (12.3 mg, 49% yield). ¹H-NMR (400 MHz, DMSO-d₆)δ(ppm): 11.21 (br s, 1H), 9.06 (br s, 1H), 7.37-7.36 (m, 1H), 7.35-7.34(m, 1H), 7.18-7.16 (m, 1H), 6.08 (s, 1H), 5.68 (s, 1H), 4.71-4.68 (m,1H), 4.60-4.56 (m, 1H), 4.46-4.44 (m, 1H), 4.02-3.96 (m, 1H), 3.78-3.74(m, 1H), 3.46 (s, 3H). MS: (ES, m/z): 361 [M+H]⁺.

Example 46—Preparation of(S)-3-ethyl-N-hydroxy-4-(tetrahydro-2H-pyran-4-carbonyl)-2,3,4,5-tetrahydrobenzo[f][1,4]oxazepine-8-carboxamide

Step-1: Methyl(S)-3-bromo-4-(((1-hydroxybutan-2-yl)amino)methyl)benzoate

Into a 500-mL round-bottom flask, was placed a solution of(2S)-2-aminobutan-1-ol (7 g, 78.53 mmol, 1.8 equiv) in MeCN (150 mL),K₂CO₃ (9 g, 65.22 mmol, 1.5 equiv) and a solution of methyl3-bromo-4-(bromomethyl)benzoate (13.5 g, 43.84 mmol, 1 equiv) in MeCN(100 mL). The resulting mixture was stirred for 14 h at room temperatureand then concentrated under vacuum. The residue was diluted with H₂O(200 mL) and extracted with EtOAc (2×200 mL). The combined organiclayers were washed with H₂O (2×200 mL) and concentrated under vacuum.The residue was purified by silica gel chromatography (EtOAc/pet. ether,1:9) to afford the title compound as an off-white solid (6.9 g, 50%yield). MS: (ES, m/z): 316 [M+H]⁺.

Step-2: Methyl(S)-3-ethyl-2,3,4,5-tetrahydrobenzo[f][1,4]oxazepine-8-carboxylate

Into a 150-mL pressure tank reactor purged and maintained with an inertatmosphere of nitrogen, was placed a solution of methyl(S)-3-bromo-4-(((1-hydroxybutan-2-yl)amino)methyl)benzoate (6.9 g, 21.82mmol, 1 equiv) in isopropanol (130 mL), K₂CO₃ (5.14 g, 37.25 mmol, 1.7equiv) and CuI (2.08 g, 10.95 mmol, 0.5 equiv). The resulting mixturewas stirred for 20 h at 110° C. in an oil bath, then was concentratedunder vacuum. The residue was diluted with H₂O (1 mL) and extracted withCH₂Cl₂ (3×100 mL). The combined organic layers were washed with H₂O(3×100 mL) and concentrated under vacuum. The residue was purified bysilica gel chromatography (EtOAc/pet. ether, 1:3) to afford the titlecompound as a green oil (2.1 g), which was used without furtherpurification. MS: (ES, m/z): 236 [M+H]⁺.

Step-3: Methyl(S)-3-ethyl-4-(tetrahydro-2H-pyran-4-carbonyl)-2,3,4,5-tetrahydrobenzo[f][1,4]oxazepine-8-carboxylate

Into a 8-mL vial, was placed a solution of oxane-4-carboxylic acid (56mg, 0.43 mmol, 1 equiv) in DMF (2.5 mL), HATU (120 mg, 0.32 mmol, 1.2equiv), methyl(S)-3-ethyl-2,3,4,5-tetrahydrobenzo[f][1,4]oxazepine-8-carboxylate (100mg, 0.43 mmol, 1 equiv), and DIEA (164 mg, 1.27 mmol, 3 equiv). Theresulting solution was stirred for 20 h at room temperature. Theresulting solution was diluted with H₂O (10 mL) and extracted with EtOAc(3×10 mL). The combined organic layers were washed with H₂O (2×10 mL)and concentrated under vacuum. The residue was purified by silica gelchromatography (EtOAc/pet. ether, 1:2) to afford the title compound as ayellow oil (100 mg, 68% yield). MS: (ES, m/z): 348 [M+H]⁺.

Step-4:(S)-3-Ethyl-N-hydroxy-4-(tetrahydro-2H-pyran-4-carbonyl)-2,3,4,5-tetrahydrobenzo[f][1,4]oxazepine-8-carboxamide

Into a 8-mL vial, were placed methyl(S)-3-ethyl-4-(tetrahydro-2H-pyran-4-carbonyl)-2,3,4,5-tetrahydrobenzo[f][1,4]oxazepine-8-carboxylate(100 mg, 0.29 mmol, 1 equiv) and THF/MeOH (4:1, 2 mL). Then NH₂OH (50%in water, 0.57 mL, 30 equiv) and aq. 1N NaOH (0.58 mL, 2 equiv) wereadded at the same time. The resulting solution was stirred for 2 h atroom temperature. The crude product was purified by Prep-HPLC (Column:Xbridge Prep C18 OBD, 5 μm, 19×150 mm; Mobile Phase A: Water/0.05%formic acid; Mobile Phase B: MeCN; Flow rate: 30 mL/min; Gradient: 15% Bto 60% B in 12 min; Detector, UV 254, 220 nm) to afford the titlecompound as an off-white solid (25.5 mg, 25% yield). ¹H-NMR (400 MHz,DMSO-d₆) δ(ppm): 11.19 (s, 1H), 7.43-7.17 (m, 3H), 4.91-4.87 (m, 0.3H),4.78-4.75 (m, 1.7H), 4.39-4.18 (m, 3H), 3.85 (m, 1H), 3.82 (m, 1H),3.41-3.36 (m, 1H), 3.14-3.13 (m, 1H), 2.93-2.89 (m, 0.3H), 2.87-2.75 (m,0.7H), 1.67-1.82 (m, 0.2H), 1.63-1.62 (m, 1.8H), 1.60-1.25 (m, 3H), 0.96(m, 1H), 0.85-0.83 (m, 2H), 0.77-0.71 (m, 1H). MS: (ES, m/z): 349[M+H]⁺.

Example 47—Preparation of(S)-3-ethyl-N-hydroxy-4-(tetrahydro-2H-pyran-4-carbonyl)-2,3,4,5-tetrahydrobenzo[f][1,4]oxazepine-8-carboxamide

Step-1: Methyl(S)-3-bromo-4-(((1-hydroxy-3-methoxypropan-2-yl)amino)methyl)benzoate

Into a 500-mL round-bottom flask, was placed(2S)-2-amino-3-methoxypropan-1-ol hydrochloride (8.5 g, 27.60 mmol, 1equiv), a solution of K₂CO₃ (20.0 g, 144.71 mmol, 5 equiv) in MeCN (150mL). This was followed by the addition of a solution of methyl3-bromo-4-(bromomethyl)benzoate (15.0 g, 105.93 mmol, 2 equiv) in MeCN(100 mL) dropwise with stirring at 0° C. The resulting solution wasstirred overnight at room temperature, then concentrated under vacuum.The residue was purified by silica gel chromatography (EtOAc/pet. ether,1:1) to afford the title compound as a yellow solid (6.5 g, 71% yield).MS: (ES, m/z): 332, 334 [M+H]⁺.

Step-2: Methyl(R)-3-(methoxymethyl)-2,3,4,5-tetrahydrobenzo[f][1,4]oxazepine-8-carboxylate

Into a 120-mL sealed tube, was placed a solution of methyl(S)-3-bromo-4-(((1-hydroxy-3-methoxypropan-2-yl)amino)methyl)benzoate(5.0 g, 15.05 mmol, 1 equiv) in isopropanol (120 mL), K₂CO₃ (3.13 g,22.48 mmol, 1.5 equiv), and CuI (0.86 g, 4.52 mmol, 0.3 equiv). Theresulting mixture was stirred overnight at 110° C. in an oil bath, thenconcentrated under vacuum. The residue was purified by silica gelchromatography (EtOAc/pet. ether, 1:1) to afford the title compound as ayellow-green oil (1 g, 26% yield). MS: (ES, m/z): 252 [M+H]⁺.

Step-3: Methyl(R)-3-(methoxymethyl)-4-(tetrahydro-2H-pyran-4-carbonyl)-2,3,4,5-tetrahydrobenzo[f][1,4]oxazepine-8-carboxylate

Into a 10-mL round-bottom flask, was placed a solution ofoxane-4-carboxylic acid (120 mg, 0.92 mmol, 1.5 equiv) in DMF (3 mL),DMTMM (332 mg, 1.20 mmol, 2 equiv) and Methyl(R)-3-(methoxymethyl)-2,3,4,5-tetrahydrobenzo[f][1,4]oxazepine-8-carboxylate(150 mg, 0.60 mmol, 1 equiv). The resulting solution was stirredovernight at room temperature. The crude product was purified byFlash-Prep-HPLC (Mobile Phase A: Water/0.05% TFA, Mobile Phase B: MeCN;Flow rate: 45 mL/min; Gradient: 5% B to 50% B in 25 min; Detector: 220,254 nm) to afford the title compound as colorless oil (60 mg, 28%yield). MS: (ES, m/z): 364 [M+H]⁺.

Step-4:(R)—N-Hydroxy-3-(methoxymethyl)-4-(tetrahydro-2H-pyran-4-carbonyl)-2,3,4,5-tetrahydrobenzo[f][1,4]oxazepine-8-carboxamide

Into a 8-mL vial, were placed methyl(R)-3-(methoxymethyl)-4-(tetrahydro-2H-pyran-4-carbonyl)-2,3,4,5-tetrahydrobenzo[f][1,4]oxazepine-8-carboxylate(60 mg, 0.17 mmol, 1 equiv) and THF/MeOH (3:1, 4 mL). Then NH₂OH (50% inwater, 1.0 mL, 100 equiv) and aq. 1N NaOH (1.0 mL, 6 equiv) were addedat the same time. The resulting solution was stirred for 1 h at roomtemperature. The crude product was purified by Prep-HPLC (Column:Xbridge Prep C18 OBD, 5 μm, 19×150 mm; Mobile Phase A: Water/0.05%formic acid; Mobile Phase B: MeCN; Flow rate: 20 mL/min; Gradient: 12% Bto 34% B in 9 min; Detector, UV 254, 220 nm) to afford the titlecompound as a yellow solid (22.7 mg, 34% yield). ¹H-NMR (400 MHz,DMSO-d₆) δ(ppm): 11.15 (br s, 1H), 7.40-7.20 (m, 3H), 4.98-4.83 (m, 2H),4.51-4.27 (m, 3H), 3.85-3.29 (m, 7H), 3.28-3.12 (m, 2H), 3.01-2.80 (m,1H), 1.72-0.80 (m, 4H). MS: (ES, m/z): 365 [M+H]⁺.

TABLE 24 The following compound was prepared according to the method ofExample 47, using (2R)-2-amino-3-methoxypropan-1-ol hydrochloride inStep 1. Found Structure M + H ¹H-NMR (400 MHz, DMSO-d₆) δ(ppm)

(ES, m/z): 365 [M + H]⁺ 11.15 (br s, 1H), 7.94 (br, 1H), 7.42-7.18 (m,3H), 4.99-4.79 (m, 2H), 4.61-4.20 (m, 3H), 3.86-3.68 (m, 2H), 3.67-3.16(m, 7H), 2.93-2.78 (m, 1H), 1.77-0.78 (m, 4H)

Example 48—Preparation of(S)-3-benzyl-N-hydroxy-4-(tetrahydro-2H-pyran-4-carbonyl)-2,3,4,5-tetrahydrobenzo[f][1,4]oxazepine-8-carboxamide

Step-1: Methyl(S)-3-bromo-4-(((1-hydroxy-3-phenylpropan-2-yl)amino)methyl)benzoate

Into a 40-mL scintillation vial was placed(S)-2-amino-3-phenylpropan-1-ol (271 mg, 1.79 mmol, 1.30 equiv), K₂CO₃(572 mg, 4.14 mmol, 3.00 equiv) and MeCN (15 ml). The resulting slurrywas cooled to 0° C. in an ice-water bath. Next, a solution of methyl3-bromo-4-(bromomethyl)benzoate (425 mg, 1.380 mmol, 1.00 equiv) in MeCN(3 mL) was added dropwise over 10 min while maintaining the internaltemperature at 0° C. The ice bath was removed and the resulting slurrywas allowed to slowly warm to room temperature. Stirring continued atroom temperature for 16 h. The reaction was concentrated under reducedpressure to remove most of the MeCN. The concentrated mixture waspartitioned between EtOAc (10 mL) and H₂O (5 ml). The organic phase waswashed with brine (5 mL), dried over Na₂SO₄, filtered and concentratedto afford the title compound as a yellow oil (628 mg), which was usedwithout further purification. MS: (ES, m/z): 379 [M+H]⁺.

Step-2: Methyl(S)-3-benzyl-2,3,4,5-tetrahydrobenzo[f][1,4]oxazepine-8-carboxylate

Into a 40-mL scintillation vial was placed methyl(S)-3-bromo-4-(((1-hydroxy-3-phenylpropan-2-yl)amino)methyl)benzoatehydrochloride (522 mg, 1.39 mmol, 1 equiv) in isopropanol (5 mL). K₂CO₃(381 mg, 2.76 mmol, 2 equiv) was added followed by CuI (52.6 mg, 0.276mmol, 0.2 equiv). The resulting solution was heated to reflux for 18 h.The resulting mixture was filtered through a celite pad and washed withisopropanol (10 mL). The filtrate was reduced in volume to −5 mL and IONHCl (1.1 equiv) was added dropwise, with stirring, to the filtrate. Theresulting slurry was cooled in an ice bath for 30 min before beingfiltered to afford the title compound as the HCl salt as a yellow solid(252 mg, 49.3% yield). ¹H-NMR (400 MHz, DMSO-d₆) δ(ppm): 7.68-7.77 (m,1H), 7.58-7.66 (m, 1H), 7.54 (d, J=1.8 Hz, 1H), 7.23-7.45 (m, 4H),4.36-4.58 (m, 2H), 4.26 (br d, J=11.4 Hz, 1H), 3.74-4.05 (m, 4H), 3.42(s, 1H), 3.07-3.27 (m, 2H), 2.90 (br dd, J=13.6, 9.2 Hz, 1H), 1.03 (d,J=6.2 Hz, 1H). MS: (ES, m/z): 298 [M+H]⁺.

Step-3: Methyl(S)-3-benzyl-4-(tetrahydro-2H-pyran-4-carbonyl)-2,3,4,5-tetrahydrobenzo[f][1,4]oxazepine-8-carboxylate

Into a 4-mL vial was placed methyl(S)-3-benzyl-2,3,4,5-tetrahydrobenzo[f][1,4]oxazepine-8-carboxylatehydrochloride (50 mg, 0.150 mmol, 1 equiv), Et₃N (0.063 ml, 0.449 mmol,3 equiv), tetrahydro-2H-pyran-4-carboxylic acid (23.4 mg, 0.180 mmol,1.2 equiv) and dichloroethane (3 mL). Next, DMC (30.4 mg, 0.180 mmol,1.2 equiv) was added and the resulting solution was stirred at roomtemperature for 4 hours. The reaction was washed with aq. 1N NaOH (1mL). The organic layer was separated, dried over Na₂SO₄, filtered andconcentrated to dryness to afford the title compound (61.4 mg, 99%yield). MS: (ES, m/z): 410 [M+H]⁺.

Step-4:(S)-3-Benzyl-N-hydroxy-4-(tetrahydro-2H-pyran-4-carbonyl)-2,3,4,5-tetrahydrobenzo[f][1,4]oxazepine-8-carboxamide

Into a 4-ml vial was placed methyl(S)-3-benzyl-4-(tetrahydro-2H-pyran-4-carbonyl)-2,3,4,5-tetrahydrobenzo[f][1,4]oxazepine-8-carboxylate(61.4 mg, 0.150 mmol, 1 equiv), NH₂OH (50% in water, 0.198 ml, 3 mmol,20 equiv), and aq. 1N NaOH (0.3 ml, 0.3 mmol, 2 equiv) in a solution ofTHF/MeOH (4:1, 1.5 mL). The resulting solution was stirred at roomtemperature for 1 h. The reaction was concentrated and the residue waspurified by Prep-HPLC (Column: Xbridge Prep C18 OBD, 5 μm, 19×50 mm;Mobile Phase A: Water/0.1% formic acid; Mobile Phase B: MeCN/0.1% formicacid; Flow rate: 23 mL/min; Gradient: 0% B to 35% B in 8 min; Detector,UV 254, 220 nm) to afford the title compound (16 mg, 26% yield). MS:(ES, m/z): 411 [M+H]⁺.

Example 49—Preparation ofN-hydroxy-4-(tetrahydro-2H-pyran-4-carbonyl)-3-(tetrahydro-2H-pyran-4-yl)-2,3,4,5-tetrahydrobenzo[f][1,4]oxazepine-8-carboxamide

Step-1: Methyl3-bromo-4-(((2-hydroxy-1-(tetrahydro-2H-pyran-4-yl)ethyl)amino)methyl)benzoate

Into a 40-mL scintillation vial was placed2-amino-2-(tetrahydro-2H-pyran-4-yl)ethanol (102 mg, 0.705 mmol, 1.3equiv), K₂CO₃ (225 mg, 1.63 mmol, 3 equiv) and MeCN (10 mL). Theresulting slurry was cooled to 0° C. in an ice-water bath. Next, asolution of methyl 3-bromo-4-(bromomethyl)benzoate (167 mg, 0.542 mmol,1 equiv) in MeCN (3 mL) was added dropwise over 10 minutes whilemaintaining the internal temperature at 0° C. The ice bath was removedand the resulting slurry was allowed to slowly warm to room temperature.Stirring continued at room temperature for 16 hours. The reaction wasconcentrated under reduced pressure to remove most of the MeCN. Theconcentrated mixture was partitioned between EtOAc (10 mL) and H₂O (5mL). The organic phase was washed with brine (5 mL), dried over Na₂SO₄,filtered, and concentrated to afford the title compound as a pale yellowoil (265 mg), which was used without further purification. MS: (ES,m/z): 373 [M+H]⁺.

Step-2: Methyl3-(tetrahydro-2H-pyran-4-yl)-2,3,4,5-tetrahydrobenzo[f][1,4]oxazepine-8-carboxylate

Into a 40-mL scintillation vial was placed methyl3-bromo-4-(((2-hydroxy-1-(tetrahydro-2H-pyran-4-yl)ethyl)amino)methyl)benzoate(202 mg, 0.542 mmol, 1 equiv) in isopropanol (5 mL). K₂CO₃ (150 mg, 1.08mmol, 2 equiv) was added followed by CuI (20.6 mg, 0.108 mmol, 0.2equiv). The resulting solution was heated to reflux for 18 h. Theresulting mixture was filtered through a celite pad and washed withisopropanol (10 mL). The filtrate was reduced in volume to −5 mL and IONHCl (1.1 equiv) was added dropwise, with stirring, to the filtrate. Theresulting slurry was cooled in an ice bath for 30 minutes before beingfiltered to afford the title compound as the HCl salt as a yellow solid(63.3 mg, 36% yield). MS: (ES, m/z): 292 [M+H]⁺.

Step-3: Methyl4-(tetrahydro-2H-pyran-4-carbonyl)-3-(tetrahydro-2H-pyran-4-yl)-2,3,4,5-tetrahydrobenzo[f][1,4]oxazepine-8-carboxylate

Into a 4-mL vial was placed methyl3-(tetrahydro-2H-pyran-4-yl)-2,3,4,5-tetrahydrobenzo[f][1,4]oxazepine-8-carboxylatehydrochloride (20 mg, 0.061 mmol, 1 equiv), Et₃N (0.024 ml, 0.183 mmol,3 equiv), tetrahydro-2H-pyran-4-carboxylic acid (9.5 mg, 0.073 mmol, 1.2equiv) and dichloroethane (3 mL). Next, DMC (12.3 mg, 0.073 mmol, 1.2equiv) was added and the resulting solution was stirred at roomtemperature for 4 hours. The reaction was washed with aq. 1N NaOH (1mL). The organic layer was separated, dried over Na₂SO₄, filtered andconcentrated to dryness to afford the title compound (24.6 mg, 99%yield). MS: (ES, m/z): 404 [M+H]⁺.

Step-4:N-Hydroxy-4-(tetrahydro-2H-pyran-4-carbonyl)-3-(tetrahydro-2H-pyran-4-yl)-2,3,4,5-tetrahydrobenzo[f][1,4]oxazepine-8-carboxamide

Into a 4-ml vial was placed methyl4-(tetrahydro-2H-pyran-4-carbonyl)-3-(tetrahydro-2H-pyran-4-yl)-2,3,4,5-tetrahydrobenzo[f][1,4]oxazepine-8-carboxylate(24.6 mg, 0.061 mmol, 1 equiv), NH₂OH (50% in water, 0.198 ml, 3 mmol,49 equiv), and aq. 1N NaOH (0.3 ml, 0.3 mmol, 4.92 equiv) in a solutionof THF/MeOH (4:1, 1.5 mL). The resulting solution was stirred at roomtemperature for 1 h. The reaction was concentrated and the residue waspurified by Prep-HPLC (Column: Xbridge Prep C18 OBD, 5 μm, 19×50 mm;Mobile Phase A: Water/0.1% formic acid; Mobile Phase B: MeCN/0.1% formicacid; Flow rate: 23 mL/min; Gradient: 0% B to 35% B in 8 min; Detector,UV 254, 220 nm) to afford the title compound (16 mg, 26% yield). MS:(ES, m/z): 405 [M+H]⁺.

Example 50—Preparation of(R)—N-hydroxy-5-isopropyl-4-(tetrahydro-2H-pyran-4-carbonyl)-2,3,4,5-tetrahydrobenzo[f][1,4]oxazepine-8-carboxamide

Step-1: tert-Butyl (2-(5-bromo-2-isobutyrylphenoxy)ethyl)carbamate

Into a 100-mL 3-necked round-bottom flask purged and maintained with aninert atmosphere of nitrogen, was placed1-(4-bromo-2-hydroxyphenyl)-2-methylpropan-1-one (5 g, 20.57 mmol, 1equiv) in DMF (30 mL), K₂CO₃ (9.2 g, 66.57 mmol, 3 equiv), potassiumiodide (3.7 g, 1 equiv), and tert-butyl N-(2-bromoethyl)carbamate (6 g,26.77 mmol, 1.2 equiv). The resulting solution was stirred overnight at50° C. in an oil bath. The reaction was then quenched by the addition ofH₂O (100 mL) and extracted with EtOAc (3×50 mL). The combined organiclayers were washed with brine (50 mL), dried over anhydrous Na₂SO₄,filtered, and concentrated under vacuum. The residue was purified bysilica gel chromatography (EtOAc/pet. ether, 1:5) to afford the titlecompound as a yellow solid (3.5 g, 44% yield). MS: (ES, m/z): 286[M−Boc+H]⁺.

Step-2: 8-Bromo-5-isopropyl-2,3,4,5-tetrahydrobenzo[f][1,4]oxazepine

Into a 100-mL round-bottom flask, was placed tert-butyl(2-(5-bromo-2-isobutyrylphenoxy)ethyl)carbamate (3 g, 7.77 mmol, 1equiv) in CH₂Cl₂ (10 mL) and TFA (2 mL). The resulting solution wasstirred overnight at room temperature, then concentrated under vacuum.The residue was dissolved in MeOH (20 mL). The pH value of the solutionwas adjusted to 7 with saturated sodium acetate solution, thenconcentrated under vacuum. To the residue was added MeOH (50 mL) andNa(CN)BH₃ (2.6 g, 41.37 mmol, 3 equiv). The resulting mixture wasstirred overnight at room temperature, then concentrated under vacuum.H₂O (50 mL) was added, and the solution was extracted with EtOAc (3×50mL). The combined organic layers were dried over anhydrous Na₂SO₄,filtered, and concentrated under vacuum to afford the title compound asyellow oil (3.5 g, 87% yield). MS: (ES, m/z): 270 [M+H]⁺.

Step-3: tert-Butyl8-bromo-5-isopropyl-2,3-dihydrobenzo[f][1,4]oxazepine-4(5H)-carboxylate

Into a 100-mL round-bottom flask, was placed8-bromo-5-isopropyl-2,3,4,5-tetrahydrobenzo[f][1,4]oxazepine (3.5 g,12.95 mmol, 1 equiv) in CH₂Cl₂ (30 mL), Et₃N (4 g, 39.53 mmol, 3 equiv)and di-tert-butyl dicarbonate (5.5 g, 25.20 mmol, 2 equiv). Theresulting solution was stirred overnight at room temperature. Thereaction was then quenched by the addition of H₂O (50 mL) and extractedwith EtOAc (3×50 mL). The combined organic layers were washed with brine(50 mL), dried over anhydrous Na₂SO₄, filtered, and concentrated undervacuum. The residue was purified by silica gel chromatography(EtOAc/pet. ether, 1:5) to afford the title compound as a white-solid (2g, 42% yield). MS: (ES, m/z): 370 [M+H]⁺.

Step-4: 4-(tert-Butyl) 8-Methyl(R)-5-isopropyl-2,3-dihydrobenzo[f][1,4]oxazepine-4,8(5H)-dicarboxylateand 4-(tert-butyl) 8-Methyl(S)-5-isopropyl-2,3-dihydrobenzo[f][1,4]oxazepine-4,8(5H)-dicarboxylate

Into a 100-mL pressure tank reactor, was placed tert-butyl8-bromo-5-(propan-2-yl)-2,3,4,5-tetrahydro-1,4-benzoxazepine-4-carboxylate(1 g, 2.70 mmol, 1 equiv) in MeOH (60 mL), Et₃N (820 mg, 8.10 mmol, 3equiv) and Pd(dppf)Cl₂ (330 mg, 0.15 equiv). To the above reactionmixture CO (g) (60 atm) was introduced. The resulting mixture wasstirred overnight at 130° C., then concentrated under vacuum. Thereaction was then quenched by the addition of H₂O (30 mL) and extractedwith EtOAc (3×30 mL). The combined organic layers were washed with brine(50 mL), dried over anhydrous Na₂SO₄, filtered, and concentrated undervacuum. The residue was purified by silica gel chromatography(EtOAc/pet. ether, 1:5) to afford the title compounds as a racemicmixture. The racemate was then purified by Prep-SFC (Column: PhenomenexLux Cellulose-4, 5 μm, 50×250 mm; Mobile Phase A: 85% CO₂, 15% MeOH;Flow rate: 150 mL/min; Detector, UV 220 nm) to afford the single isomersas white solids (first eluting isomer: 200 mg, 21% yield; second elutingisomer: 300 mg, 32% yield). MS: (ES, m/z): 350 [M+H]⁺.

Step-5: Methyl(R)-5-isopropyl-2,3,4,5-tetrahydrobenzo[f][1,4]oxazepine-8-carboxylate

Into a 50-mL round-bottom flask, was placed the first eluting isomerfrom Step 4 (4-(tert-butyl) 8-Methyl(R)-5-isopropyl-2,3-dihydrobenzo[f][1,4]oxazepine-4,8(5H)-dicarboxylate)(200 mg, 0.57 mmol, 1 equiv), CH₂Cl₂ (8 mL), and TFA (2 mL). Theresulting solution was stirred for 3 h at room temperature, thenconcentrated under vacuum to afford the title compound as the TFA saltas yellow oil (200 mg), which was used without further purification. MS:(ES, m/z): 250 [M+H]⁺.

Step-6: Methyl(R)-5-isopropyl-4-(tetrahydro-2H-pyran-4-carbonyl)-2,3,4,5-tetrahydrobenzo[f][1,4]oxazepine-8-carboxylate

Into a 10-mL round-bottom flask, was placed methyl(R)-5-isopropyl-2,3,4,5-tetrahydrobenzo[f][1,4]oxazepine-8-carboxylate·TFA(100 mg, 0.40 mmol, 1 equiv), CH₂Cl₂ (2 mL), Et₃N (100 mg, 0.99 mmol, 4equiv) and oxane-4-carbonyl chloride (83 mg, 0.56 mmol, 2 equiv). Theresulting solution was stirred for 2 h at room temperature. The reactionwas then quenched with H₂O (30 mL) and extracted with CH₂Cl₂ (3×15 mL).The combined organic layers were washed with brine (20 mL), dried overanhydrous Na₂SO₄, filtered, and concentrated under vacuum to afford thetitle compound as a yellow oil (100 mg, 69% yield). MS: (ES, m/z): 362[M+H]⁺.

Step-7:(R)—N-Hydroxy-5-isopropyl-4-(tetrahydro-2H-pyran-4-carbonyl)-2,3,4,5-tetrahydrobenzo[f][1,4]oxazepine-8-carboxamide

Into a 10-mL round-bottom flask, was placed methyl(R)-5-isopropyl-4-(tetrahydro-2H-pyran-4-carbonyl)-2,3,4,5-tetrahydrobenzo[f][1,4]oxazepine-8-carboxylate(100 mg, 0.28 mmol, 1 equiv), MeOH/THF (1:4, 2 mL), NH₂OH (50% in water,1.4 g, 60 equiv), aq. 1N NaOH (0.6 mL, 2 equiv). The resulting solutionwas stirred for 2 h at room temperature. The solids were filtered out.The crude product was purified by Prep-HPLC (Column: Sunfire C18 OBD, 5μm, 19×150 mm; Mobile Phase A: Water/0.05% formic acid; Mobile Phase B:MeCN; Flow rate: 25 mL/min; Gradient: 15% B to 39% B in 6 min; Detector,UV 254, 220 nm) to afford the title compound as a white solid (21.2 mg,19% yield). ¹H-NMR (DMSO, 300 MHz) δ (ppm): 11.20 (s, 1H), 7.51-7.22 (m,3H), 5.14-5.11 (d, J=11.4 Hz, 1H), 4.62-4.58 (d, J=11.1 Hz, 1H),4.43-4.39 (d, J=13.2 Hz, 1H), 4.12-3.66 (m, 3H), 3.63-3.27 (m, 3H),3.21-2.91 (m, 1H), 2.50-2.49 (m, 1H), 1.65-1.18 (m, 4H), 0.93-0.82 (m,3H), 0.67-0.60 (m, 3H). MS: (ES, m/z): 363 [M+H]⁺.

TABLE 25 The following compound was prepared according to the method ofExample 50, using the second eluting isomer of the Step 4 product inStep 5. Found Structure M + H ¹H-NMR (300 MHz, DMSO-d₆) δ(ppm)

(ES, m/z): 363 [M + H]⁺ 11.13 (s, 1H), 7.51-7.23 (m, 3H), 5.14-5.11 (d,J = 11.1 Hz, 1H), 4.62-4.58 (d, J = 10.8 Hz, 1H), 4.43- 4.39 (d, J =15.6 Hz, 1H), 4.13-3.71 (m, 3H), 3.66- 3.32 (m, 3H), 3.29-2.91 (m, 1H),2.52-2.50 (m, 1H), 1.65-1.17 (m, 4H), 0.93-0.91 (d, J = 6.3 Hz, 1H),0.84-0.82 (d, J = 6.3 Hz, 2H), 0.67-0.60 (m, 3H)

Example 51—Preparation of(R)—N-hydroxy-5-isopropyl-4-(oxetane-3-carbonyl)-2,3,4,5-tetrahydrobenzo[f][1,4]oxazepine-8-carboxamide

Step-1: Methyl(R)-5-isopropyl-4-(oxetane-3-carbonyl)-2,3,4,5-tetrahydrobenzo[f][1,4]oxazepine-8-carboxylate

Into a 10-mL round-bottom flask, was placed the product from Example 45Step 5 (methyl(R)-5-isopropyl-2,3,4,5-tetrahydrobenzo[f][1,4]oxazepine-8-carboxylate·TFA)(50 mg, 0.20 mmol, 1 equiv) in DMF (3 mL), DIEA (103 mg, 0.80 mmol, 4equiv), HATU (115 mg, 0.30 mmol, 1.5 equiv) and oxetane-3-carboxylicacid (24 mg, 0.24 mmol, 1.2 equiv). The resulting solution was stirredovernight at room temperature. The reaction was then quenched with H₂O(20 mL) and extracted with EtOAc (3×15 mL). The combined organic layerswere washed with brine (20 mL), dried over anhydrous Na₂SO₄, filtered,and concentrated under vacuum to afford the title compound as yellow oil(60 mg, 90% yield). MS: (ES, m/z): 334 [M+H]⁺.

Step-2:(R)—N-Hydroxy-5-isopropyl-4-(oxetane-3-carbonyl)-2,3,4,5-tetrahydrobenzo[f][1,4]oxazepine-8-carboxamide

Into a 10-mL round-bottom flask, was placed methyl(R)-5-isopropyl-4-(oxetane-3-carbonyl)-2,3,4,5-tetrahydrobenzo[f][1,4]oxazepine-8-carboxylate(60 mg, 0.18 mmol, 1 equiv), MeOH/THF (1:4, 1 mL), NH₂OH (50% in water,711 mg, 60 equiv), aq. 1N NaOH (0.4 mL, 2 equiv). The resulting solutionwas stirred for 2 h at room temperature. The solids were filtered out.The crude product was purified by Prep-HPLC (Column: Sunfire C18 OBD, 5μm, 19×150 mm; Mobile Phase A: Water/0.05% formic acid; Mobile Phase B:MeCN; Flow rate: 25 mL/min; Gradient: 5% B to 60% B in 8 min; Detector,UV 254, 220 nm) to afford the title compound as a white solid (6.6 mg,11% yield). ¹H-NMR (DMSO, 400 MHz) δ (ppm): 11.20 (br s, 1H), 9.06-9.05(br s, 1H), 7.40-7.28 (m, 3H), 5.15-5.12 (d, J=11.2 Hz, 0.5H), 4.90-4.87(m, 0.5H), 4.76-4.55 (m, 4H), 4.49-4.15 (m, 3H), 3.92-3.89 (d, J=10.8Hz, 0.5H), 3.62-3.37 (m, 2.5H), 0.88-0.86 (m, 3H), 0.64-0.60 (t, J=7 Hz,3H). MS: (ES, m/z): 335 [M+H]⁺.

TABLE 26 The following compound was prepared according to the method ofExample 51, using the second eluting isomer of the Example 45 Step 4product. Found Structure M + H ¹H-NMR (400 MHz, DMSO-d₆) δ(ppm)

(ES, m/z): 335 [M + H]⁺ 11.19 (br s, 1H), 9.06-9.05 (br s, 1H),7.43-7.28 (m, 3H), 5.15-5.12 (d, J = 11.6 Hz, 0.5H), 4.90-4.87 (m,0.5H), 4.77-4.55 (m, 4H), 4.49-4.15 (m, 3H), 3.92- 3.89 (d, J = 10.8 Hz,0.5H), 3.64-3.38 (m, 2.5H), 0.88-0.86 (m, 3H), 0.64-0.60 (t, J = 7 Hz,3H)

Example 52—Preparation of(R)—N-hydroxy-5-methyl-4-(1-methylcyclobutane-1-carbonyl)-2,3,4,5-tetrahydrobenzo[f][1,4]oxazepine-8-carboxamide

Step-1: tert-Butyl (2-(2-acetyl-5-bromophenoxy)ethyl)carbamate

Into a 500-mL 3-necked round-bottom flask, was placed1-(4-bromo-2-hydroxyphenyl)ethan-1-one (30 g, 139 mmol, 1 equiv) in DMF(150 mL), K₂CO₃ (29 g, 209 mmol, 1.5 equiv), potassium iodide (23.2 g, 1equiv) and tert-butyl N-(2-bromoethyl)carbamate (47 g, 209 mmol, 1.5equiv). The resulting mixture was stirred overnight at 50° C. The solidswere filtered out. The filtrate was quenched with of H₂O (50 mL) andextracted with EtOAc (5×100 mL). The combined organic layers were washedwith brine (3×50 mL), dried over anhydrous Na₂SO₄, filtered, andconcentrated under vacuum. The residue was triturated with a solution ofEtOAc/pet. ether (1:10, 100 mL) to afford the title compound as anoff-white solid (42 g, 84% yield). MS: (ES, m/z): 358 [M+H]⁺.

Step-2: 8-Bromo-5-methyl-2,3-dihydrobenzo[f][1,4]oxazepine

Into a 500-mL round-bottom flask, was placed tert-butyl2-(2-acetyl-5-bromophenoxy)ethylcarbamate (23 g, 64.20 mmol, 1 equiv) inCH₂Cl₂ (100 mL) and TFA (25 mL). The resulting solution was stirredovernight at room temperature, then concentrated under vacuum to affordthe title compound as a yellow solid (15.4 g), which was used withoutfurther purification. MS: (ES, m/z): 240 [M+H]⁺.

Step-3: 8-Bromo-5-methyl-2,3,4,5-tetrahydrobenzo[f][1,4]oxazepine

Into a 500-mL round-bottom flask, was placed a solution of8-bromo-5-methyl-2,3-dihydrobenzo[f][1,4]oxazepine (15.4 g, 64.14 mmol,1 equiv) in MeOH (200 mL). The pH value of the solution was adjusted to7 with anhydrous NaOAc at 0° C. Then Na(CN)BH₃ (18.1 g, 288 mmol, 4.5equiv) was added at 0° C. The resulting mixture was stirred for 4 h atroom temperature and concentrated under vacuum. H₂O (50 mL) was added tothe residue and the solids were collected by filtration to afford thetitle compound as a white solid (15 g). MS: (ES, m/z): 242 [M+H]⁺.

Step-4: tert-Butyl8-bromo-5-methyl-2,3-dihydrobenzo[f][1,4]oxazepine-4(5H)-carboxylate

Into a 500-mL round-bottom flask, was placed tert-butyl8-bromo-5-methyl-2,3-dihydrobenzo[f][1,4]oxazepine-4(5H)-carboxylate (9g, 37.17 mmol, 1 equiv) in CH₂Cl₂ (80 mL), Et₃N (11.25 g, 111 mmol, 3equiv) and di-tert-butyl dicarbonate (12.1 g, 55.44 mmol, 1.5 equiv).The resulting solution was stirred overnight at room temperature, thenconcentrated under vacuum. The crude product was purified byFlash-Prep-HPLC (Column: silica gel; Mobile Phase A: pet. ether, MobilePhase B: EtOAc; Gradient: 0% B to 10% B in 50 min; Detector: 254 nm) toafford the title compound as white solid (11 g, 86% yield). MS: (ES,m/z): 342 [M+H]⁺.

Step-5: 4-(tert-Butyl) 8-ethyl(R)-5-methyl-2,3-dihydrobenzo[f][1,4]oxazepine-4,8(5H)-dicarboxylate and4-(tert-butyl) 8-ethyl(S)-5-methyl-2,3-dihydrobenzo[f][1,4]oxazepine-4,8(5H)-dicarboxylate

Into a 50-mL sealed tube, was placed tert-butyl8-bromo-5-methyl-2,3-dihydrobenzo[f][1,4]oxazepine-4(5H)-carboxylate((2.5 g, 7.33 mmol, 1 equiv) in EtOH (25 mL), Et₃N (2.22 g, 22 mmol, 3equiv) and Pd(dppf)Cl₂ (0.534 g, 0.73 mmol, 0.1 equiv). To the abovereaction mixture CO (g) (60 atm) was introduced. The resulting mixturewas stirred overnight at 120° C., then concentrated under vacuum. Thecrude product was purified by Flash-Prep-HPLC (Column: silica gel;Mobile Phase A: pet. ether, Mobile Phase B: EtOAc; Gradient: 0% B to 10%B in 30 min; Detector: 254 nm) to afford the title compounds as aracemic mixture. The racemate was then purified by Prep-SFC (Column:(R,R) WHELK-01 Kromasil, 10 μm, 21.1×250 mm; Mobile Phase A: 75% CO₂,25% isopropanol (0.2% N,N-diethylaniline); Flow rate: 45 mL/min;Detector, UV 254 nm) to afford the single isomers as a light yellow oil(first eluting isomer: 540 mg, 21.9% yield; second eluting isomer: 680mg, 27.7% yield). MS: (ES, m/z): 336 [M+H]⁺.

Step-6: Ethyl(R)-5-methyl-2,3,4,5-tetrahydrobenzo[f][1,4]oxazepine-8-carboxylate

Into a 25-mL round-bottom flask, was placed the first eluting isomerfrom Step 5 (4-(tert-butyl) 8-ethyl(R)-5-methyl-2,3-dihydrobenzo[f][1,4]oxazepine-4,8(5H)-dicarboxylate)(540 mg, 1.61 mmol, 1 equiv), CH₂Cl₂ (5 mL), and TFA (2 mL). Theresulting solution was stirred overnight at room temperature, thenconcentrated under vacuum. The crude product was purified byFlash-Prep-HPLC (Column: C18 silica gel; Mobile Phase A: H₂O/0.05% TFA,Mobile Phase B: MeCN; Gradient: 5% B to 50% B in 30 min; Detector: 254nm) to afford the title compound as a white solid (450 mg), which wasused without further purification. MS: (ES, m/z): 236 [M+H]⁺.

Step-7: Ethyl(R)-5-methyl-4-(1-methylcyclobutane-1-carbonyl)-2,3,4,5-tetrahydrobenzo[f][1,4]oxazepine-8-carboxylate

Into a 50-mL round-bottom flask, was placed ethyl(R)-5-methyl-2,3,4,5-tetrahydrobenzo[f][1,4]oxazepine-8-carboxylate (100mg, 0.43 mmol, 1 equiv), DMF (2 mL), HATU (194 mg, 0.51 mmol, 1.2equiv), DIEA (165 mg, 1.28 mmol, 3 equiv) and1-methylcyclobutane-1-carboxylic acid (48.6 mg, 0.43 mmol, 1 equiv). Theresulting solution was stirred overnight at room temperature. Thereaction was then quenched with H₂O (2 mL) and extracted with EtOAc(3×10 mL). The combined organic layers were washed with brine (3×5 mL),dried over anhydrous Na₂SO₄, filtered, and concentrated under vacuum.The crude product was purified by Flash-Prep-HPLC (Column: C18 silicagel; Mobile Phase A: pet. ether, Mobile Phase B: EtOAc; Gradient: 0% Bto 30% B in 25 min; Detector: 254 nm) to afford the title compound as ayellow oil (90 mg, 64% yield). MS: (ES, m/z): 332 [M+H]⁺.

Step-8:(R)—N-Hydroxy-5-methyl-4-(1-methylcyclobutane-1-carbonyl)-2,3,4,5-tetrahydrobenzo[f][1,4]oxazepine-8-carboxamide

Into a 25-mL round-bottom flask, was placed ethyl(R)-5-methyl-4-(1-methylcyclobutane-1-carbonyl)-2,3,4,5-tetrahydrobenzo[f][1,4]oxazepine-8-carboxylate(90 mg, 0.27 mmol, 1 equiv), MeOH/THF (1:4, 1.5 mL), NH₂OH (50% inwater, 1.077 g, 16.2 mmol, 60 equiv), aq. 1N NaOH (0.54 mL, 2 equiv).The resulting solution was stirred for 5 h at room temperature. The pHvalue of the solution was adjusted to 6 with 6N HCl at 0° C. The crudeproduct was purified by Prep-HPLC (Column: Sunfire C18 OBD, 5 μm, 19×150mm; Mobile Phase A: Water/0.05% formic acid; Mobile Phase B: MeCN; Flowrate: 25 mL/min; Gradient: 10% B to 40% B in 12 min; Detector, UV 254nm) to afford the title compound as a white solid (44.8 mg, 52% yield).¹H-NMR (DMSO, 400 MHz) δ (ppm): 11.15 (br s, 1H), 9.04 (br s, 1H),7.42-7.32 (m, 3H), 5.72-4.84 (m, 1H), 4.60-4.38 (m, 1H), 3.83-3.56 (m,2H), 2.40-2.23 (m, 2H), 1.92-1.76 (m, 3H), 1.61-1.20 (m, 7H). MS: (ES,m/z): 319 [M+H]⁺.

TABLE 27 The following compound was prepared according to the method ofExample 52. Found Structure M + H ¹H-NMR (300 MHz, DMSO-d₆) δ(ppm)

(ES, m/z): 335 [M + H]⁺ 11.14 (br, 1H), 9.05 (br s, 1H), 7.56-7.30 (m,3H), 5.74-5.38 (m, 1H), 4.56-4.06 (m, 2H), 3.88-3.33 (m, 4H), 3.11-2.87(m, 1H), 1.62-1.19 (m, 7H)

TABLE 28 The following compound was prepared according to the method ofExample 52, using the second eluting isomer of the Step 5 product. FoundStructure M + H ¹H-NMR (400 MHz, DMSO-d₆) δ(ppm)

(ES, m/z): 319 [M + H]⁺ 11.15 (br s, 1H), 9.05 (br s, 1H), 7.42-7.32 (m,3H), 5.72-4.37 (m, 1H), 4.39-4.37 (m, 2H), 3.80-3.56 (m, 2H), 2.50-2.22(m, 2H), 1.92-1.76 (m, 3H), 1.61-1.30 (m, 7H)

(ES, m/z): 335 [M + H]⁺ 11.14 (s, 1H), 9.07 (s, 1H), 7.56-7.30 (m, 3H),5.74- 5.38 (m, 1H), 4.56-4.06 (m, 2H), 3.88-3.50 (m, 4H), 3.11-2.86 (m,1H), 1.63-1.20 (m, 7H)

(ES, m/z): 349 [M + H]⁺ 11.16 (s, 1H), 9.01 (s, 1H), 7.39-7.29 (m, 3H),5.60- 5.56 (m, 1H), 4.39-4.30 (m, 2H), 3.81-3.36 (m, 6H), 1.99-1.94 (m,2H), 1.50-1.41 (m, 5H), 1.14 (s, 3H)

(ES, m/z): 321 [M + H]⁺ 11.17 (s, 1H), 9.04 (s, 1H), 7.41-7.32 (m, 3H),5.74- 5.72 (m, 0.5H), 4.81-4.72 (m, 1.5H), 4.62-4.58 (m, 1H), 4.45-4.33(m, 2H), 4.26-4.21 (m, 1.5H), 3.87- 3.70 (m, 1.5H), 3.36-3.01 (m, 1H),1.56-1.48 (m, 6H)

(ES, m/z): 307 [M + H]⁺ 11.30-10.60 (br s, 1H), 9.40-8.60 (br s, 1H),7.46-7.31 (m, 3H), 5.77-5.71 (m, 0.5H), 4.87-4.84 (m, 0.5H), 4.73-4.10(m, 6.5H), 3.76-3.60 (m, 1.5H), 3.45-3.38 (m, 1H), 1.51-1.47 (m, 3H)

Example 53—Preparation of(S)—N-hydroxy-4-(3-(methoxymethyl)oxetane-3-carbonyl)-5-methyl-2,3,4,5-tetrahydrobenzo[f][1,4]oxazepine-8-carboxamide

Step-1: Ethyl(S)-4-(3-(hydroxymethyl)oxetane-3-carbonyl)-5-methyl-2,3,4,5-tetrahydrobenzo[f][1,4]oxazepine-8-carboxylate

Into a 25-mL round-bottom flask, was placed ethyl(S)-5-methyl-2,3,4,5-tetrahydrobenzo[f][1,4]oxazepine-8-carboxylate(from the second eluting isomer of Example 47 Step 5) (150 mg, 0.64mmol, 1 equiv) in DMF (5 mL), HATU (269 mg, 0.71 mmol, 1.5 equiv), DIEA(413 mg, 3.20 mmol, 5 equiv) and 3-(hydroxymethyl)oxetane-3-carboxylicacid (84 mg, 0.64 mmol, 1 equiv). The resulting solution was stirredovernight at room temperature. The reaction was then quenched with waterand extracted with EtOAc (3×10 mL). The combined organic layers werewashed with brine (2×5 mL), dried over anhydrous Na₂SO₄, filtered, andconcentrated under vacuum. The residue was purified by silica gelchromatography (EtOAc/pet. ether, 1:4) to afford the title compound as ayellow oil (160 mg, 72% yield). MS: (ES, m/z): 350 [M+H]⁺.

Step-2: Ethyl(S)-4-(3-(methoxymethyl)oxetane-3-carbonyl)-5-methyl-2,3,4,5-tetrahydrobenzo[f][1,4]oxazepine-8-carboxylate

Into a 8-mL round-bottom flask, was placed ethyl(S)-4-(3-(hydroxymethyl)oxetane-3-carbonyl)-5-methyl-2,3,4,5-tetrahydrobenzo[f][1,4]oxazepine-8-carboxylate(100 mg, 0.29 mmol, 1 equiv), THE (2 mL), and sodium hydride (17.2 mg,0.72 mmol, 2.5 equiv). After stirred for 30 min at room temperature,iodomethane (65 mg, 0.46 mmol, 1.6 equiv) was added. The resultingsolution was stirred for 2 h at room temperature. The reaction was thenquenched with aq. NH₄Cl at 0° C. The crude product was purified byFlash-Prep-HPLC (Column: C18 silica gel; Mobile Phase A: H₂O/0.05% TFA,Mobile Phase B: MeCN; Gradient: 0% B to 50% B in 30 min; Detector: 254nm) to afford the title compound as a white solid (80 mg, 83% yield).MS: (ES, m/z): 364 [M+H]⁺.

Step-3:(S)—N-hydroxy-4-(3-(methoxymethyl)oxetane-3-carbonyl)-5-methyl-2,3,4,5-tetrahydrobenzo[f][1,4]oxazepine-8-carboxamide

Into a 25-mL round-bottom flask, was placed ethyl(S)-4-(3-(methoxymethyl)oxetane-3-carbonyl)-5-methyl-2,3,4,5-tetrahydrobenzo[f][1,4]oxazepine-8-carboxylate(80 mg, 0.24 mmol, 1 equiv) in DMA (1 mL), isopropyl chloroformate (36.5mg, 1 equiv), 4-methylmorpholine (30.2 mg, 0.30 mmol, 1 equiv),NH₂OH·HCl (20.6 mg, 1 equiv). The resulting mixture was stirredovernight at room temperature. The crude product was purified byPrep-HPLC (Column: Xbridge Prep C18 OBD, 5 μm, 19×50 mm; Mobile Phase A:Water/0.05% formic acid; Mobile Phase B: MeCN; Flow rate: 23 mL/min;Gradient: 5% B to 48% B in 7 min; Detector, UV 254, 220 nm) to affordthe title compound as an off-white solid (5.9 mg, 7% yield). ¹H-NMR(DMSO, 400 MHz) δ (ppm): 11.18 (s, 1H), 9.05 (s, 1H), 7.43-7.32 (m, 3H),5.72-5.70 (m, 0.6H), 4.74-4.31 (m, 6H), 3.88-3.69 (m, 3.4H), 3.40-3.05(m, 4H), 1.50-1.48 (d, 3H). MS: (ES, m/z): 351 [M+H]⁺.

Example 54T—Preparation of(S)—N-hydroxy-5-methyl-4-((S)-3-methyltetrahydrofuran-3-carbonyl)-2,3,4,5-tetrahydrobenzo[f][1,4]oxazepine-8-carboxamideand(S)—N-hydroxy-5-methyl-4-((R)-3-methyltetrahydrofuran-3-carbonyl)-2,3,4,5-tetrahydrobenzo[f][1,4]oxazepine-8-carboxamide

Step-1: Ethyl(S)-5-methyl-4-((S)-tetrahydro-2H-pyran-3-carbonyl)-2,3,4,5-tetrahydrobenzo[f][1,4]oxazepine-8-carboxylateand ethyl(S)-5-methyl-4-((R)-tetrahydro-2H-pyran-3-carbonyl)-2,3,4,5-tetrahydrobenzo[f][1,4]oxazepine-8-carboxylate

Into a 8-mL round-bottom flask, was placed ethyl(S)-5-methyl-2,3,4,5-tetrahydrobenzo[f][1,4]oxazepine-8-carboxylate(from the second eluting isomer of Example 47 Step 5) (200 mg, 0.85mmol, 1 equiv) in DMF (4 mL), HATU (388 mg, 1.02 mmol, 1.2 equiv), DIEA(330 mg, 2.55 mmol, 3 equiv) and oxane-3-carboxylic acid (166 mg, 1.28mmol, 1.5 equiv). The resulting solution was stirred overnight at roomtemperature. The reaction was then quenched with water. The resultingsolution was extracted with EtOAc (3×5 mL). The combined organic layerswere washed with brine (2×5 mL), dried over anhydrous Na₂SO₄, filtered,and concentrated under vacuum. The residue was purified by silica gelchromatography (EtOAc/pet. ether, 1:3) to afford the racemic mixture ofthe title compounds as a yellow oil (150 mg). The racemate was separatedby Chiral-Prep-HPLC (Column Chiralpak IC, 5 μm, 2×25 cm; Mobile Phase A:hexanes; Mobile Phase B: EtOH; Gradient: 30% B for 21 min; Flow rate: 20mL/min; Detector, UV 254, 220 nm) to afford the single isomers of titlecompounds as yellow oils (first eluting isomer: 20 mg, 7% yield; secondeluting isomer: 20 mg, 7% yield). MS: (ES, m/z): 348 [M+H]⁺.

Step-2:(S)—N-Hydroxy-5-methyl-4-((S)-3-methyltetrahydrofuran-3-carbonyl)-2,3,4,5-tetrahydrobenzo[f][1,4]oxazepine-8-carboxamideand(S)—N-hydroxy-5-methyl-4-((R)-3-methyltetrahydrofuran-3-carbonyl)-2,3,4,5-tetrahydrobenzo[f][1,4]oxazepine-8-carboxamide

Into 8-mL vials, was placed each of the separated isomers from Step 1(20 mg, 0.06 mmol; and 20 mg, 0.06 mmol; 1 equiv) in THF/MeOH (4; 1, 1mL). Then aq. 1N NaOH (0.12 mL, 2 equiv) and NH₂OH (50% in H₂O, 475 mg,3.6 mmol, 60 equiv) were added. The resulting solution was stirred for 1h at room temperature. The pH value of the solutions was adjusted to 6with 6N HCl at 0° C. The solids were filtered out. The crude productswere purified by Flash-Prep-HPLC (Column: C18 silica gel, 5 μm, 19×150mm; Mobile Phase A: Water/0.1% formic acid; Mobile Phase B: MeCN; Flowrate: 0.7 mL/min; Gradient: 5% B to 60% B in 7 min; Detector, UV 254,220 nm) to afford the title compounds as off-white solids. The productfrom the reaction with the first eluting isomer of Step 1: (7.8 mg, 41%yield). ¹H-NMR (400 MHz, DMSO-d₆) δ(ppm): 11.15 (br s, 1H), 9.05-9.04(br s, 1H), 7.56-7.29 (m, 3H), 5.71-5.31 (m, 1H), 4.52-4.02 (m, 2H),4.07-3.24 (m, 6H), 2.97-2.83 (m, 1H), 1.97-1.44 (m, 7H). MS: (ES, m/z):335 [M+H]⁺. The product from the reaction with the second eluting isomerof Step 1: (12 mg, 66% yield). ¹H-NMR (400 MHz, DMSO-d₆) δ(ppm): 11.15(br s, 1H), 9.05 (br s, 1H), 7.53-7.29 (m, 3H), 5.72-5.40 (m, 1H),4.53-4.02 (m, 2H), 3.89-3.23 (m, 6H), 3.11-2.80 (m, 1H), 1.89-1.43 (m,7H). MS: (ES, m/z): 335 [M+H]⁺.

TABLE 29 The following compounds were prepared according to the methodof Example 54. Found Structure M + H ¹H-NMR (400 MHz, DMSO-d₆) δ(ppm)

(ES, m/z): 321 [M + H]⁺ 11.12 (br s, 1H), 9.05 (br s, 1H), 7.56-7.31 (m,3H), 5.74-5.36 (m, 1H), 4.57-4.02 (m, 2H), 3.93-3.33 (m, 7H), 2.23-1.90(m, 2H), 1.57-1.46 (m, 3H)

(ES, m/z): 321 [M + H]⁺ 11.13 (br s, 1H), 9.06 (br s, 1H), 7.56-7.31 (m,3H), 5.75-5.32 (m, 1H), 4.53-3.53 (m, 8H), 3.35-3.33 (m, 1H), 2.08-1.79(m, 2H), 1.56-1.47 (m, 3H)

(ES, m/z): 363 [M + H]⁺ 11.14 (br s, 1H), 7.54-2.29 (m, 3H), 5.73-5.33(m, 1H), 4.54-4.01 (m, 2H), 3.80-3.76 (m, 1H), 3.53- 3.21 (m, 1H),3.22-3.21 (m, 3H), 3.08-3.02 (m, 1H), 2.78-2.50 (m, 1H), 2.01-1.91 (m,2H), 1.75-1.70 (m, 1H), 1.58-1.10 (m, 8H)

(ES, m/z): 363 [M + H]⁺ 11.16 (br s, 1H), 8.99 (br s, 1H), 7.53-7.30 (m,3H), 5.73-5.32 (m, 1H), 4.54-4.01 (m, 2H), 3.80-3.36 (m, 3H), 3.17 (s,1H), 2.83-2.62 (m, 1H), 1.83-1.76 (m, 2H), 1.63-1.38 (m, 8H), 1.26-1.03(m, 1H)

(ES, m/z): 335 [M + H]⁺ 11.16 (br s, 1H), 9.05 (br, 1H), 7.42-7.32 (m,3H), 5.80-5.00 (m, 1H), 4.42-4.39 (m, 1H), 3.88-3.56 (m, 7H), 2.23 (br,1H), 1.89 (br, 1H), 1.52-1.50 (d, 3H), 1.28 (s, 3H)

(ES, m/z): 335 [M + H]⁺ 11.12 (br s, 1H), 9.05 (br s, 1H), 7.51-7.28 (m,3H), 5.61-5.22 (m, 1H), 4.41-4.39 (m, 1H), 3.90-3.55 (m, 7H), 2.33-1.95(m, 1H), 1.52-1.26 (m, 6H)

(ES, m/z): 349 [M + H]⁺ 11.20 (br s, 1H), 7.42-7.31 (m, 3H), 5.60-5.55(m, 1H), 4.41-4.26 (m, 2H), 3.78-3.60 (m,. 4H), 3.38- 3.29 (m, 2H),1.79-1.73 (m, 2H), 1.65-1.57 (m, 1H), 1.47-1.39 (m, 4H), 1.22 (s, 3H)

(ES, m/z): 349 [M + H]⁺ 11.18 (br s, 1H), 8.80-7.50 (br s, 1H),7.42-7.31 (m, 3H), 5.59-5.53 (m, 1H), 4.41-4.25 (m, 2H), 3.80- 3.75 (m,1H), 3.68-3.58 (m, 3H), 3.37-3.31 (m, 2H), 1.86-1.80 (m, 2H), 1.63-1.36(m, 5H), 1.22 (s, 3H)

Example 55—Preparation of(S)—N-hydroxy-4-(4-(methoxymethyl)tetrahydro-2H-pyran-4-carbonyl)-5-methyl-2,3,4,5-tetrahydrobenzo[f][1,4]oxazepine-8-carboxamide

Step-1: Ethyl(S)-4-(4-(methoxymethyl)tetrahydro-2H-pyran-4-carbonyl)-5-methyl-2,3,4,5-tetrahydrobenzo[f][1,4]oxazepine-8-carboxylate

Into a 50-mL 3-necked round-bottom flask purged and maintained with aninert atmosphere of nitrogen, was placed1-(methoxymethyl)cyclohexane-1-carboxylic acid (147 mg, 0.85 mmol, 2equiv), CH₂Cl₂ (2 mL), DMF (1 drop), then oxalyl chloride (2 mL) wasadded at 0° C., and stirred for 2 h at room temperature. The solvent wasevaporated to afford 1-(methoxymethyl)cyclohexanecarbonyl chloride. Intoanother 50-mL 3-necked round-bottom flask purged and maintained with aninert atmosphere of nitrogen, was placed 4-dimethylaminopyridine (51.7mg, 0.85 mmol, 1 equiv), Et₃N (172 mg, 1.70 mmol, 4 equiv), ethyl(S)-5-methyl-2,3,4,5-tetrahydrobenzo[f][1,4]oxazepine-8-carboxylate(from the second eluting isomer of Example 47 Step 5) (100 mg, 0.43mmol, 1 equiv) and CH₂Cl₂ (2 mL). Then a solution of1-(methoxymethyl)cyclohexanecarbonyl chloride in CH₂Cl₂ (2 mL) was addeddropwise at 0° C. The resulting solution stirred for an additional 4 hat room temperature, then concentrated under vacuum. The crude productwas purified by Flash-Prep-HPLC (Column: C18 silica gel; Mobile Phase A:pet. ether, Mobile Phase B: EtOAc; Gradient: 0% B to 20% B in 30 min;Detector: 254 nm) to afford the title compound as a yellow oil (90 mg,54% yield). MS: (ES, m/z): 392 [M+H]⁺.

Step-2:(S)—N-Hydroxy-4-(4-(methoxymethyl)tetrahydro-2H-pyran-4-carbonyl)-5-methyl-2,3,4,5-tetrahydrobenzo[f][1,4]oxazepine-8-carboxamide

Into a 25-mL round-bottom flask, was placed ethyl(S)-4-(4-(methoxymethyl)tetrahydro-2H-pyran-4-carbonyl)-5-methyl-2,3,4,5-tetrahydrobenzo[f][1,4]oxazepine-8-carboxylate(90 mg, 0.23 mmol, 1 equiv), THF/MeOH (4:1, 0.5 mL), NH₂OH (50% inwater, 910 mg, 13.8 mmol, 60 equiv), aq. 1N NaOH (0.46 mL, 0.46 mmol, 2equiv). The resulting solution was stirred for 1.5 h at roomtemperature. The pH value of the solution was adjusted to 6 with 6N HClat 0° C. The crude product was purified by Prep-HPLC (Column: Gemini-NXC18 110 Å, AXIA Packed, 5 μm, 21.2×150 mm; Mobile Phase A: Water/0.05%formic acid; Mobile Phase B: MeCN; Flow rate: 20 mL/min; Gradient: 5% Bto 57% B in 8 min; Detector, UV 254, 220 nm) to afford the titlecompound as a white solid (19.7 mg, 23% yield). ¹H-NMR (400 MHz,DMSO-d₆) δ(ppm): 11.17 (s, 1H), 9.02 (br s, 1H), 7.42-7.30 (m, 3H),5.58-5.56 (m, 1H), 4.40-4.31 (m, 2H), 3.75-3.53 (m, 5H), 3.46-3.29 (m,3H), 3.12 (s, 3H), 2.70-1.96 (m, 2H), 1.62-1.55 (m, 5H). MS: (ES, m/z):379 [M+H]⁺.

Example 56—Preparation of(R)—N-hydroxy-5-methyl-4-(1-methylcyclobutane-1-carbonyl)-2,3,4,5-tetrahydrobenzo[f][1,4]oxazepine-7-carboxamide

Step-1: tert-Butyl (2-(2-acetyl-4-bromophenoxy)ethyl)carbamate

Into a 500-mL 3-necked round-bottom flask, was placed a solution of1-(5-bromo-2-hydroxyphenyl)ethan-1-one (30 g, 139.51 mmol, 1 equiv),K₂CO₃ (29 g, 209.83 mmol, 3 equiv), potassium iodide (23.2 g, 1 equiv)and tert-butyl N-(2-bromoethyl)carbamate (37.5 g, 167.34 mmol, 1.2equiv) in DMF (150 mL). The resulting solution was stirred overnight at50° C. in an oil bath. The reaction mixture was cooled to 0° C. andquenched with H₂O (50 mL). The resulting solution was extracted withCH₂Cl₂ (2×100 mL), washed with brine (5×100 mL) and dried over anhydrousNa₂SO₄. The solids were filtered out and the filtrate was concentratedunder vacuum. The crude product was purified by silica gelchromatography (Gradient 0 EtOAc/pet. ether over 50 min) to afford thetitle compound as a light yellow solid (39 g, 78% yield). MS: (ES, m/z):358 [M+H]⁺.

Step-2: 7-Bromo-5-methyl-2,3-dihydrobenzo[f][1,4]oxazepine

Into a 500-mL round-bottom flask, was placed tert-butylN-[2-(2-acetyl-4-bromophenoxy)ethyl]carbamate (20 g, 55.83 mmol, 1equiv), CH₂Cl₂ (100 mL) and TFA (20 mL). The resulting solution wasstirred overnight at room temperature. The resulting mixture wasconcentrated under vacuum to afford the title compound as a red solid(20 g) which was used without further purification. MS: (ES, m/z): 240[M+H]⁺.

Step-3: 7-Bromo-5-methyl-2,3,4,5-tetrahydro-1,4-benzoxazepine

Into a 500-mL round-bottom flask, was placed a solution of7-bromo-5-methyl-2,3-dihydrobenzo[f][1,4]oxazepine (10 g, 38.74 mmol, 1equiv) in MeOH (100 mL), the pH value of the solution was adjusted to 7with anhydrous sodium acetate at 0° C. Then Na(CN)BH₃ (7.9 g, 113.52mmol, 3 equiv) was added at 0° C. The resulting solution was stirred for2 h at room temperature. The resulting mixture was concentrated undervacuum and 20 mL of water was added. The solids were collected byfiltration to afford the title compound as a white solid (7 g, 75%yield) which was used without further purification. MS: (ES, m/z): 242[M+H]⁺.

Step-4: tert-Butyl7-bromo-5-methyl-2,3,4,5-tetrahydro-1,4-benzoxazepine-4-carboxylate

Into a 50-mL round-bottom flask, was placed7-bromo-5-methyl-2,3,4,5-tetrahydro-1,4-benzoxazepine (2 g, 8.26 mmol, 1equiv), CH₂Cl₂ (20 mL), Et₃N (2.51 g, 24.80 mmol, 3 equiv),di-tert-butyl dicarbonate (2.71 g, 12.42 mmol, 1.5 equiv). The resultingsolution was stirred overnight at room temperature. The resultingmixture was concentrated under vacuum. The crude product was purified bysilica gel chromatography (Gradient 0-30% EtOAc/pet. ether over 20 min)to afford the title compound as a light yellow oil (2.4 g, 85% yield).MS: (ES, m/z): 342 [M+H]⁺.

Step-5: 4-(tert-Butyl) 7-ethyl(R)-5-methyl-2,3-dihydrobenzo[f][1,4]oxazepine-4,7(5H)-dicarboxylate

Into a 50-mL pressure tank reactor, was placed tert-butyl7-bromo-5-methyl-2,3,4,5-tetrahydro-1,4-benzoxazepine-4-carboxylate (2.4g, 7.01 mmol, 1 equiv), ethanol (40 mL), Et₃N (2.1 g, 20.75 mmol, 3equiv), and Pd(dppf)Cl₂ (515.1 mg, 0.70 mmol, 0.1 equiv). CO (g) (60atm) was introduced and the resulting solution was stirred overnight at120° C. The solids were filtered out and the filtrate was concentratedunder vacuum and purified by silica gel chromatography (Gradient 0-10%EtOAc/pet. ether over 30 min) to afford the racemic mixture of the titlecompounds, which were separated by Prep-SFC (Column Chiralpak IC OBD, 5μm, 5×250 mm; Mobile Phase: 75% CO₂, 25% Isopropanol; Flow rate: 170mL/min; Detector, UV 254, 220 nm) to afford the single isomers of thetitle compounds as light yellow oils (first eluting isomer: 440 mg, 19%yield; second eluting isomer: 500 mg, 21% yield). MS: (ES, m/z): 336[M+H]⁺.

Step-6: Ethyl(R)-5-methyl-2,3,4,5-tetrahydrobenzo[f][1,4]oxazepine-7-carboxylate

Into a 50-mL round-bottom flask, was placed the first eluting isomerfrom Step 5 (4-(tert-butyl) 7-ethyl(R)-5-methyl-2,3-dihydrobenzo[f][1,4]oxazepine-4,7(5H)-dicarboxylate)(440 mg, 1.31 mmol, 1 equiv), CH₂Cl₂ (5 mL), and TFA (2 mL). Theresulting solution was stirred overnight at room temperature andconcentrated under vacuum. The crude product was purified by silica gelchromatography (Gradient 10-50% EtOAc/pet. ether over 30 min) to affordthe title compound as a light yellow oil (300 mg, 97% yield). MS: (ES,m/z): 236 [M+H]⁺.

Step-7: Ethyl(R)-5-methyl-4-(1-methylcyclobutane-1-carbonyl)-2,3,4,5-tetrahydrobenzo[f][1,4]oxazepine-7-carboxylate

Into a 50-mL round-bottom flask, was placed1-methylcyclobutane-1-carboxylic acid (48.6 mg, 0.43 mmol, 1 equiv), DMF(2 mL), ethyl(R)-5-methyl-2,3,4,5-tetrahydrobenzo[f][1,4]oxazepine-7-carboxylate (100mg, 0.43 mmol, 1 equiv), HATU (194.4 mg, 0.51 mmol, 1.2 equiv), and DIEA(165.2 mg, 1.28 mmol, 3 equiv). The resulting solution was stirredovernight at room temperature. The reaction was then quenched with H₂O(2 mL) and extracted with EtOAc (3×10 mL). The combined organic layerswere washed with brine (3×5 mL) and dried over anhydrous Na₂SO₄,filtered, and concentrated under vacuum. The residue was purified bysilica gel chromatography (Gradient 0-30% EtOAc/pet. ether over 25 min)to afford the title compounds as a yellow oil (80 mg, 57% yield). MS:(ES, m/z): 332 [M+H]⁺.

Step-8:(R)—N-hydroxy-5-methyl-4-(1-methylcyclobutane-1-carbonyl)-2,3,4,5-tetrahydrobenzo[f][1,4]oxazepine-7-carboxamide

Into a 8-mL round-bottom flask, was placed ethyl(R)-5-methyl-4-(1-methylcyclobutane-1-carbonyl)-2,3,4,5-tetrahydrobenzo[f][1,4]oxazepine-7-carboxylate(40 mg, 0.12 mmol, 1 equiv), and THF/MeOH (4:1, 1.5 mL). This wasfollowed by the addition of aq. 1N NaOH (0.24 mL, 2 equiv) and NH₂OH(50% in water, 478 mg, 60 equiv). The resulting solution was stirred for2.5 h at room temperature. The pH value of the solution was adjusted to6 with 6N HCL. The crude product was purified by Prep-HPLC (Column:Sunfire Prep C18 OBD, 5 μm, 19×150 mm; Mobile Phase A: Water/0.05% oTFA; Mobile Phase B: MeCN; Flow rate: 25 mL/min; Gradient: 5% o B to 35%o B in 7 min; Detector: UV 254, 220 nm) to afford the title compound asan off-white solid (11 mg, 220 yield). ¹H-NMR (400 MHz, DMSO-d₆) δ(ppm):11.22-11.10 (s, 1H), 7.68 (s, 1H), 7.58-7.56 (d, 1H), 7-6.92 (d, 2H),5.73-5.70 (d, 2H), 4.94-4.83 (d, 1H), 4.67-4.60 (d, 1H), 4.40-4.37 (d,2H), 3.86-3.57 (8, 2H), 2.40-2.24 (m, 2H), 1.92-1.78 (m, 3H),1.63-1.1.45 (m, 4H), 1.36-1.33 (m, 3H). MS: (ES, m/z): 319 [M+H]⁺.

TABLE 30 The following compounds were prepared according to the methodof Example 56. Found Structure M + H ¹H-NMR (400 MHz, DMSO-d₆) δ(ppm)

(ES, m/z): 335 [M + H]⁺ 11.25-11.12 (s, 1H), 8.99-8.94 (s, 1H),7.87-7.67 (m, 1H), 7.67-7.55 (d, 1H), 7-6.98 (d, 1H), 5.78-5.37 (m, 1H),4.55-4.09 (m, 2H), 3.88-3.70 (m, 4H), 3.50-3.37 (m, 2H), 3.17-2.87 (m,1H), 1.63-1.19 (m, 7H)

TABLE 31 The following compounds were prepared according to the methodof Example 56, using the second eluting isomer of the Step 5 product.Found Structure M + H ¹H-NMR (400 MHz, DMSO-d₆) δ(ppm)

(ES, m/z): 319 [M + H]⁺ 11.22-11.10 (s, 1H), 7.68 (s, 1H), 7.58-7.56 (d,1H), 7- 6.92 (d, 1H), 5.73-5.70 (m, 1H), 4.94-4.83 (d, 0.5H), 4.67-4.60(m, 0.5H), 4.40-4.37 (m, 1H), 3.86-3.27 (m, 2H), 2.51-2.22 (m, 2H),1.92-1.77 (m, 3H), 1.63-1.45 (m, 4H), 1.36-1.24 (m, 3H)

(ES, m/z): 335 [M + H]⁺ 11.25-11.12 (s, 1H), 9.50-8.50 (br, 1H),7.87-7.67 (d, 1H), 7.67-7.55 (d, 1H), 7.01-6.98 (d, 1H), 5.76-5.37 (m,1H), 4.55-4.05 (m, 2H), 3.84-3.30 (m, 6H), 3.11-2.86 (m, 1H), 1.63-1.20s(m, 7H)

Example 57—Preparation of(2R,5R)—N-Hydroxy-4-(tetrahydro-2H-pyran-4-carbonyl)-2,3,4,5-tetrahydro-2,5-methanobenzo[f][1,4]oxazepine-8-carboxamide

Step-1: Ethyl 7-hydroxy-4-oxo-4H-chromene-2-carboxylate

Into a 1000-mL round-bottom flask, was placed ethanol (300 mL). This wasfollowed by the addition of sodium (18 g, 783 mmol, 6 equiv), inportions and stirred at room temperature until the sodium was completelydissolved. To this was added 1-(2,4-dihydroxyphenyl)ethan-1-one (20 g,131 mmol, 1 equiv), in portions. To the mixture was added diethyloxalate (56 g, 383 mmol, 3 equiv) dropwise with stirring. The resultingsolution was stirred for 2 h at 85° C. in an oil bath. Then 6N HCl (aq.)was added at room temperature and the resulting mixture was stirred for10 min. The resulting mixture was extracted with CH₂Cl₂ (3×150 mL),dried over anhydrous MgSO₄, filtered, and concentrated under vacuum. Theresidue was dissolved in ethanol (200 mL). To the solution was addedconc. HCl (6 mL). The resulting solution was stirred for 2 h at 85° C.in an oil bath. The product was precipitated by the addition of EtOAc(50 mL). The solids were collected by filtration to afford the titlecompound as a light yellow solid (21 g, 68% yield). MS: (ES, m/z): 235[M+H]⁺.

Step-2: Ethyl 7-hydroxy-4-oxochroman-2-carboxylate

Into a 1000-mL pressure tank reactor (10 atm), was placed a solution ofethyl 7-hydroxy-4-oxo-4H-chromene-2-carboxylate (10 g, 42.7 mmol, 1equiv) in ethanol (600 mL) and Raney nickel (2 g). Hydrogen gas wasintroduced and the resulting solution was stirred overnight at 80° C. inan oil bath. The solids were filtered out. The resulting mixture wasconcentrated under vacuum and purified by silica gel chromatography(EtOAc/pet. ether, 1:3) to afford the title compound as a white solid (6g, 59% yield). MS: (ES, m/z): 237 [M+H]⁺.

Step-3:7-Hydroxy-4-oxochroman-2-carboxylic acid

Into a 250-mL round-bottom flask, was placed a solution of ethyl7-hydroxy-4-oxochroman-2-carboxylate (12 g, 50.8 mmol, 1 equiv) in THE(50 mL). This was followed by the addition of a solution of NaOH (6.1 g,152 mmol, 3 equiv) in water (50 mL) dropwise with stirring. Theresulting solution was stirred for 4 h at room temperature. The pH valueof the solution was adjusted to 1 with 3N HCl. The resulting solutionwas extracted with EtOAc (3×100 mL), dried over anhydrous Na₂SO₄ andconcentrated under vacuum to afford the title compound as a light yellowsolid (10.5 g, 99% yield). MS: (ES, m/z): 209 [M+H]⁺.

Step-4: N-Benzyl-7-hydroxy-4-oxochroman-2-carboxamide

Into a 250-mL round-bottom flask, was placed a solution of7-hydroxy-4-oxochroman-2-carboxylic acid (10.5 g, 50 mmol, 1 equiv) inDMF (90 mL). This was followed by the addition of HATU (23 g, 60 mmol,1.2 equiv), in portions. To this was added phenylmethanamine (5.9 g, 55mmol, 1.1 equiv) and DIEA (19.5 g, 150 mmol, 3 equiv) dropwise withstirring. The resulting solution was stirred overnight at roomtemperature. The reaction was then quenched by the addition of water(300 mL). The resulting solution was extracted with EtOAc (3×400 mL).The combined organic layers were dried over anhydrous Na₂SO₄,concentrated under vacuum and purified by silica gel chromatography(EtOAc/pet. ether, 2:1) to afford the title compound as a white solid(11 g, 73% yield). MS: (ES, m/z): 298 [M+H]⁺.

Step-5:4-Benzyl-2,3,4,5-tetrahydro-2,5-methanobenzo[f][1,4]oxazepin-8-ol

Into a 500-mL round-bottom flask purged and maintained with an inertatmosphere of nitrogen, was placed a solution of sodiumbis(2-methoxyethoxy)aluminum hydride solution (Red-Al®) (14.6 g, 51mmol, 3 equiv, 70% in toluene). This was followed by the addition of asolution of N-benzyl-7-hydroxy-4-oxochroman-2-carboxamide (5 g, 17 mmol,1 equiv) in THE (100 mL) dropwise with stirring at 0° C. The resultingsolution was stirred for 4 h at 70° C. in an oil bath. The reaction wasthen quenched by the addition of saturated aqueous solution of potassiumsodium tartrate tetrahydrate (100 mL) and extracted with EtOAc (3×150mL). The combined organic layers were dried over anhydrous Na₂SO₄,concentrated under vacuum and purified by silica gel chromatography(EtOAc/pet. ether, 1:2) to afford the title compound as a light yellowsolid (1 g, 22% yield). MS: (ES, m/z): 268 [M+H]⁺.

Step-6:4-Benzyl-2,3,4,5-tetrahydro-2,5-methanobenzo[f][1,4]oxazepin-8-yltrifluoromethanesulfonate

Into a 100-mL round-bottom flask, were placed a solution of4-benzyl-2,3,4,5-tetrahydro-2,5-methanobenzo[f][1,4]oxazepin-8-ol (1.5g, 5.61 mmol, 1 equiv) in CH₂Cl₂ (50 mL) and triethylamine (1.1 g, 10.89mmol, 2 equiv). This was followed by the addition of(trifluoromethane)sulfonyl trifluoromethanesulfonate (2.4 g, 8.51 mmol,1.5 equiv) dropwise with stirring at 0° C. The resulting solution wasstirred for 2 h at 0° C. The reaction was then quenched by the additionof water (20 mL). The resulting mixture was washed with water (2×30 mL),dried over anhydrous MgSO₄, concentrated under vacuum and purified bysilica gel chromatography (EtOAc/pet. ether, 1:5) to afford the titlecompound as a light yellow oil (1.2 g, 54% yield). MS: (ES, m/z): 400[M+H]⁺.

Step-7: Ethyl(2R,5R)-4-benzyl-2,3,4,5-tetrahydro-2,5-methanobenzo[f][1,4]oxazepine-8-carboxylateand Ethyl(2S,5S)-4-benzyl-2,3,4,5-tetrahydro-2,5-methanobenzo[f][1,4]oxazepine-8-carboxylate

Into a 250-mL pressure tank reactor (50 atm) purged and maintained withan atmosphere of carbon monoxide, were placed a mixture of4-benzyl-2,3,4,5-tetrahydro-2,5-methanobenzo[f][1,4]oxazepin-8-yltrifluoromethanesulfonate (2.2 g, 5.51 mmol, 1 equiv) in ethanol (180mL), triethylamine (1.7 g, 16.80 mmol, 3 equiv) and Pd(dppf)Cl₂CH₂Cl₂(0.45 g, 0.1 equiv). The resulting mixture was stirred overnight at 120°C. in an oil bath. The solids were filtered out. The resulting mixturewas concentrated under vacuum. The residue was dissolved in EtOAc (100mL), washed with water (2×100 mL), dried over anhydrous sodium sulfateand concentrated under vacuum. The residue was purified by silica gelchromatography (EtOAc/pet. ether, 1:5) to afford a racemic mixture ofthe title compounds as a light yellow oil (1.2 g, 67% yield). ¹H-NMR(400 MHz, DMSO-d₆) δ(ppm): 7.55-7.42 (m, 2H), 7.36-7.24 (m, 5H),6.94-6.81 (m, 1H), 4.93-4.82 (m, 1H), 4.36 (q, J=7.2 Hz, 2H), 3.99-3.83(m, 1H), 3.66-3.55 (m, 1H), 3.50-3.30 (m, 2H), 2.70-2.55 (m, 1H),2.35-2.11 (m, 2H), 1.38 (t, J=7.2 Hz, 3H). MS: (ES, m/z): 324 [M+H]⁺.

800 mg of the racemic mixture was separated by prep-SFC (Column:Chiralpak AD-H, 5 μm, 5×25 cm; Mobile Phase A: CO₂, Mobile Phase B: MeOH(0.2% N,N-diethylaniline); Flow rate: 150 mL/min; Detector, UV 254 nm)to afford the single isomers of the title compounds as light yellow oils(first eluting isomer: 360 mg; second eluting isomer: 430 mg). MS: (ES,m/z): 324 [M+H]⁺.

Step-8: Ethyl(2R,5R)-2,3,4,5-tetrahydro-2,5-methanobenzo[f][1,4]oxazepine-8-carboxylate

Into a 25-mL round-bottom flask purged and maintained with an atmosphereof hydrogen, was placed a solution of the first eluting isomer from Step7 (ethyl(2R,5R)-4-benzyl-2,3,4,5-tetrahydro-2,5-methanobenzo[f][1,4]oxazepine-8-carboxylate)(80 mg, 0.25 mmol, 1 equiv) in MeOH (5 mL) and palladium on carbon.Hydrogen gas was introduced and the resulting solution was stirred for 3h at room temperature. The solids were filtered out. The resultingmixture was concentrated under vacuum to afford the title compound as alight yellow oil (50 mg, 87% yield). MS: (ES, m/z): 234 [M+H]⁺.

Step-9: Ethyl(2R,5R)-4-(tetrahydro-2H-pyran-4-carbonyl)-2,3,4,5-tetrahydro-2,5-methanobenzo[f][1,4]oxazepine-8-carboxylate

Into a 8-mL vial, were placed a solution of oxane-4-carboxylic acid (28mg, 0.22 mmol, 1 equiv) in DMF (2 mL), HATU (98 mg, 0.26 mmol, 1.2equiv), ethyl(2R,5R)-2,3,4,5-tetrahydro-2,5-methanobenzo[f][1,4]oxazepine-8-carboxylate(50 mg, 0.21 mmol, 1 equiv), and DIEA (89 mg, 0.69 mmol, 3 equiv). Theresulting solution was stirred overnight at room temperature. Thereaction was then quenched with water (5 mL) and extracted with EtOAc(3×15 mL). The combined organic layers were dried over anhydrous Na₂SO₄,filtered, and concentrated under vacuum. The residue was purified bysilica gel chromatography (EtOAc/pet. ether, 2:1) to afford the titlecompound as a light yellow oil (45 mg, 61% yield). MS: (ES, m/z): 346[M+H]⁺.

Step-10:(2R,5R)—N-Hydroxy-4-(tetrahydro-2H-pyran-4-carbonyl)-2,3,4,5-tetrahydro-2,5-methanobenzo[f][1,4]oxazepine-8-carboxamide

Into a 8-mL vial, was placed a solution of ethyl(2R,5R)-4-(tetrahydro-2H-pyran-4-carbonyl)-2,3,4,5-tetrahydro-2,5-methanobenzo[f][1,4]oxazepine-8-carboxylate(45 mg, 0.13 mmol, 1 equiv) in THF/MeOH (4:1, 1 mL). A. 1N NaOH (0.26mL, 2 equiv) and NH₂OH (50% in water, 0.24 mL, 30 equiv) were addedsimultaneously. The resulting solution was stirred for 2 h at roomtemperature. The crude product was purified by Prep-HPLC (Column:XBridge Prep C18 OBD, 5 μm, 19×150 mm; Mobile Phase A: Water/0.1% formicacid, Mobile Phase B: MeCN; Gradient: 5% B to 26% B in 8 min; Detector:UV, 254 nm, 220 nm) to afford the title compound as an off-white solid(7.8 mg, 18% yield). ¹H-NMR (400 MHz, DMSO-d₆) δ(ppm): 11.05 (br s, 1H),9.01 (br s, 1H), 7.45-7.28 (m, 1H), 7.26-7.00 (m, 2H), 5.38-4.97 (m,2H), 3.93-3.74 (m, 3H), 3.62-3.36 (m, 2H), 3.29-2.91 (m, 2H), 2.32-1.99(m, 2H), 1.71-1.13 (m, 4H). MS: (ES, m/z): 333 [M+H]⁺.

TABLE 32 The following compound was prepared according to the method ofExample 57, using the second eluting isomer of the Step 7 product. FoundStructure M + H ¹H-NMR (400 MHz, DMSO-d₆) δ(ppm)

(ES, m/z): 333 [M + H]⁺ 11.10 (br s, 1H), 9.00 (s, 1H), 7.39-7.20 (m,2H), 7.18- 7.01 (m, 2H), 5.30-5.07 (m, 2H), 3.88-3.76 (m, 3H), 3.64-3.43(m, 2H), 3.43-3.01 (m, 1H), 2.31-2.02 (m, 2H), 1.64-1.16 (m, 4H)

Example 58—Preparation of4-(cyclohexanecarbonyl)-N-hydroxy-2,3,4,5-tetrahydropyrido[2,3-f][1,4]oxazepine-8-carboxamide

Step-1: Methyl 5-bromo-6-iodopyridine-3-carboxylate

Into a 1000-mL round-bottom flask, was placed methyl5-bromo-6-chloropyridine-3-carboxylate (11 g, 43.92 mmol, 1 equiv), MeCN(330 mL), trimethylsilyl iodide (8.767 g, 1 equiv) and sodium iodide(19.7 g, 3 equiv). The resulting mixture was stirred for 4 h at 25° C.and then concentrated. The residue was diluted with H₂O (300 mL). The pHvalue of the solution was adjusted to 7 with 2N NaOH. The solids werecollected by filtration to afford the title compound as a yellow solid(16 g) which was used without further purification. MS: (ES, m/z): 250[M+H]⁺.

Step-2: Methyl 5-bromo-6-methylpyridine-3-carboxylate

Into a 250-mL 3-necked round-bottom flask purged and maintained with aninert atmosphere of nitrogen, was placed methyl5-bromo-6-iodopyridine-3-carboxylate (6 g, 17.55 mmol, 1 equiv),1,4-dioxane (60 mL), trimethyl-1,3,5,2,4,6-trioxatriborinane (15 mL, 50%in THF, 3 equiv), Pd(dppf)Cl₂CH₂Cl₂ (1.44 g, 0.1 equiv) and potassiumcarbonate (7.34 g, 53.10 mmol, 3 equiv). The resulting solution wasstirred for 72 h at 75° C. in an oil bath. The reaction mixture wascooled to room temperature. The solids were filtered out. The filtratewas diluted with EtOAc (100 mL), washed with brine (3×30 mL), dried overanhydrous Na₂SO₄, filtered, and concentrated. The residue was purifiedby silica gel chromatography (EtOAc/pet. ether, 1:10) to afford thetitle compound as an off-white solid (3 g, 74% yield). MS: (ES, m/z):230 [M+H]⁺.

Step-3: Methyl 5-bromo-6-(bromomethyl)pyridine-3-carboxylate

Into a 250-mL 3-necked round-bottom flask purged and maintained with aninert atmosphere of nitrogen, was placed methyl5-bromo-6-methylpyridine-3-carboxylate (3 g, 13.04 mmol, 1 equiv), CCl₄(60 mL), NBS (2.435 g, 13.68 mmol, 1.05 equiv) and benzoyl peroxide (158mg, 0.62 mmol, 0.05 equiv). The resulting mixture was stirred for 16 hat 80° C. in an oil bath. The reaction mixture was cooled to roomtemperature. The solids were filtered out. The filtrate was concentratedand diluted with EtOAc (150 mL), washed with brine (3×50 mL). Theorganic phase was dried over anhydrous Na₂SO₄, filtered, andconcentrated to afford the title compound as a brown oil (2.5 g) whichwas used without further purification. MS: (ES, m/z): 310 [M+H]⁺.

Step-4: Methyl5-bromo-6-[[(2-hydroxyethyl)amino]methyl]pyridine-3-carboxylate

Into a 250-mL round-bottom flask, was placed MeCN (50 mL),2-aminoethan-1-ol (990 mg, 16.21 mmol, 2 equiv) and potassium carbonate(2.26 g, 16.32 mmol, 2 equiv). This was followed by the addition of asolution of methyl 5-bromo-6-(bromomethyl)pyridine-3-carboxylate (2.5 g,4.86 mmol, 1 equiv 60%) in MeCN (20 mL) dropwise with stirring at 0° C.The resulting solution was stirred for additional 2 h at 0° C. Thesolids were filtered out. The filtrate was concentrated. The residue waspurified by silica gel chromatography (CH₂Cl₂/MeOH, 20:1) to afford thetitle compound as a yellow solid (0.7 g, 50% yield). MS: (ES, m/z): 289[M+H]⁺.

Step-5: Methyl5-bromo-6-(((tert-butoxycarbonyl)(2-hydroxyethyl)amino)methyl)nicotinate

Into a 25-mL round-bottom flask, was placed methyl5-bromo-6-[[(2-hydroxyethyl)amino]methyl]pyridine-3-carboxylate (500 mg,1.73 mmol, 1 equiv), THE (10 mL), di-tert-butyl dicarbonate (416 mg,1.91 mmol, 1.10 equiv), and Et₃N (350 mg, 3.47 mmol, 2 equiv). Theresulting mixture was stirred for 1 h at 25° C. and then concentrated.The residue was purified by silica gel chromatography (EtOAc/pet. ether,1:3) to afford the title compound as a yellow-green oil (0.55 g, 82%yield). MS: (ES, m/z): 389 [M+H]⁺.

Step-6: 4-(tert-Butyl) 8-methyl2,3-dihydropyrido[2,3-f][1,4]oxazepine-4,8(5H)-dicarboxylate

Into a 100-mL 3-necked round-bottom flask purged and maintained with aninert atmosphere of nitrogen, was placed Pd(OAc)₂ (87 mg, 0.39 mmol,0.05 equiv), Johnphos (0.184 g, 0.08 equiv), Cs₂CO₃ (3.784 g, 11.61mmol, 1.5 equiv) and 1,4-dioxane (30 mL). This was followed by theaddition of a solution of methyl5-bromo-6-(((tert-butoxycarbonyl)(2-hydroxyethyl)amino)methyl)nicotinate(3 g, 7.71 mmol, 1 equiv) in 1,4-dioxane (20 mL). The resulting mixturewas stirred for 16 h at 95° C. in an oil bath. The reaction mixture wascooled to room temperature and diluted with EtOAc (50 mL) and H₂O (50mL). The resulting solution was washed with brine (3×50 mL). The organicphase was dried over anhydrous Na₂SO₄, filtered, and concentrated. Theresidue was purified by silica gel chromatography (CH₂Cl₂/MeOH, 20:1) toafford the title compound as an orange solid (1.2 g, 50% yield). MS:(ES, m/z): 309 [M+H]⁺.

Step-7: Methyl2,3,4,5-tetrahydropyrido[2,3-f][1,4]oxazepine-8-carboxylate

Into a 100-mL round-bottom flask, was placed 4-(tert-butyl) 8-methyl2,3-dihydropyrido[2,3-f][1,4]oxazepine-4,8(5H)-dicarboxylate (1.2 g,3.89 mmol, 1 equiv), CH₂C₁₂ (40 mL) and TFA (5 mL). The resultingsolution was stirred for 2 h at 25° C. The pH value of the solution wasadjusted to 7-8 with sodium bicarbonate. The solution was dried overanhydrous Na₂SO₄, filtered, and concentrated. The residue was purifiedby silica gel chromatography (CH₂Cl₂/MeOH, 10:1) to afford the titlecompound as an orange solid (0.6 g, 74% yield). ¹H-NMR (400 MHz,DMSO-d₆) δ(ppm): 8.88 (s, 1H), 7.90 (s, 1H), 4.23 (s, 2H), 4.12-4.08 (t,2H), 3.94 (s, 3H), 3.30-3.17 (t, 2H). MS: (ES, m/z): 209 [M+H]⁺.

Step-8: Methyl4-(cyclohexanecarbonyl)-2,3,4,5-tetrahydropyrido[2,3-f][1,4]oxazepine-8-carboxylate

Into a 25-mL round-bottom flask, was placed methyl2,3,4,5-tetrahydropyrido[2,3-f][1,4]oxazepine-8-carboxylate (50 mg, 0.24mmol, 1 equiv), CH₂Cl₂ (2 mL), cyclohexanecarbonyl chloride (38 mg, 0.26mmol, 1.1 equiv) and Et₃N (72 mg, 0.71 mmol, 3 equiv). The resultingmixture was stirred for 1 h at 25° C. and concentrated. The residue wasdiluted with water (10 mL) and extracted with CH₂Cl₂ (3×10 ml). Theorganic layer was dried over Na₂SO₄, filtered, and concentrated undervacuum. The residue was purified by silica gel chromatography(EtOAc/pet. ether, 1:3) to afford the title compound as a light yellowoil (60 mg, 78% yield). MS: (ES, m/z): 319 [M+H]⁺.

Step-9:4-(Cyclohexanecarbonyl)-N-hydroxy-2,3,4,5-tetrahydropyrido[2,3-f][1,4]oxazepine-8-carboxamide

Into a 10-mL round-bottom flask, was placed methyl4-(cyclohexanecarbonyl)-2,3,4,5-tetrahydropyrido[2,3-f][1,4]oxazepine-8-carboxylate(68 mg, 0.21 mmol, 1 equiv), THF/MeOH (4:1, 2.5 mL), aq. 1N NaOH (0.428mL, 2 equiv) and NH₂OH (50% in water, 0.212 mL, 30 equiv). The resultingsolution was stirred for 1 h at 25° C. The pH value of the solution wasadjusted to 6 with 1N HCl. The crude product was purified by Prep-HPLC(Column: HSS C18 OBD, 1.8 μm, 2.1×50 mm; Mobile Phase A: Water/0.05%TFA; Mobile Phase B: MeCN/0.05% TFA; Flow rate: 0.7 mL/min; Gradient: 5%B to 95% B in 2 min, hold 0.6 min; Detector: UV 254, 220 nm) to affordthe title compound as an off-white solid (47 mg, 70% yield). ¹H-NMR (300MHz, DMSO-d₆) δ(ppm): 11.34 (s, 1H), 8.53 (d, 1H), 8.48 (d, 1H), 4.84(d, 2H), 4.64 (t, 1H), 4.54 (t, 1H), 3.88 (m, 2H), 2.62 (s, 1H), 1.52(s, 4H), 1.37 (s, 1H), 1.06-1.26 (m, 5H). MS: (ES, m/z): 320 [M+H]⁺.

Example 59—Preparation of4-(cyclohexanecarbonyl)-N-hydroxy-2,3,4,5-tetrahydropyrido[3,2-f][1,4]oxazepine-8-carboxamide

Step-1: 2-(Methoxycarbonyl)-5-methylpyridine 1-oxide

Into a 3 L 3-necked round-bottom flask, was placed methyl5-methylpicolinate (43.7 g, 289 mmol, 1 equiv) and CH₂Cl₂ (1 L). Thiswas followed by the addition of 3-chlorobenzene-1-carboperoxoic acid(106 g, 614 mmol, 2 equiv) in several batches at 0° C. The resultingmixture was stirred for overnight at room temperature. The reaction wasthen quenched with sat. aq. Na₂SO₃ (500 mL) and extracted with CH₂Cl₂(3×100 mL) The combined organic layers were washed with sat. aq. NaHCO₃solution (400 mL), dried over anhydrous Na₂SO₄, filtered, andconcentrated under vacuum. The crude product was re-crystallized frompet. ether:CH₂Cl₂ (20:1) to afford the title compound as a yellow solid(40 g, 83% yield). MS: (ES, m/z): 168 [M+H]⁺.

Step-2: Methyl 6-chloro-5-methylpyridine-2-carboxylate

Into a 100-mL round-bottom flask, was placed2-(methoxycarbonyl)-5-methylpyridine 1-oxide (10 g, 59.82 mmol, 1 equiv)and chloroform (50 mL), followed by the addition of phosphoryltrichloride (42.2 mL, 9 equiv) dropwise with stirring. The resultingsolution was stirred overnight at 80° C. in an oil bath. The resultingmixture was concentrated under vacuum and then quenched with water (20mL). The pH value of the solution was adjusted to 7 with K₂CO₃ (10% inwater) and extracted with EtOAc (3×20 mL). The combined organic layerswere washed with H₂O (3×20 mL), dried over anhydrous Na₂SO₄, filtered,and concentrated under vacuum. The residue was purified by silica gelchromatography (Gradient 0-10% MeOH/CH₂Cl₂) to afford the title compoundas a yellow solid (7 g, 57% yield). ¹H-NMR (400 MHz, DMSO-d₆) δ(ppm):7.96-8.02 (m, 2H), 3.88 (s, 1H), 2.41-2.51 (m, 3H). MS: (ES, m/z): 186[M+H]⁺.

Step-3: Methyl 5-(bromomethyl)-6-chloropyridine-2-carboxylate

Into a 100-mL round-bottom flask purged and maintained with an inertatmosphere of nitrogen, was placed methyl6-chloro-5-methylpyridine-2-carboxylate (4.2 g, 22.63 mmol, 1 equiv),benzoyl peroxide (549.9 mg, 2.27 mmol, 0.1 equiv), NBS (4.04 g, 22.70mmol, 1 equiv) and CCl₄ (35 mL). The resulting mixture was stirredovernight at 80° C. in an oil bath. The reaction was concentrated undervacuum and quenched with water (20 mL), then extracted with EtOAc (3×30mL). The combined organic layers were washed with H₂O (3×20 mL), anddried over anhydrous Na₂SO₄, filtered, and concentrated under vacuum.The residue was purified by silica gel chromatography (Gradient 0-10%MeOH/CH₂Cl₂) to afford the title compound as a yellow solid (2.5 g, 38%yield). MS: (ES, m/z): 265 [M+H]⁺.

Step-4: Methyl 6-chloro-5-(((2-hydroxyethyl)amino)methyl)picolinate

Into a 50-mL round-bottom flask, was placed a solution of2-aminoethan-1-ol (1.4 g, 22.89 mmol, 2 equiv) in MeCN (20 mL) and K₂CO₃(4.74 g, 34.03 mmol, 3 equiv). This was followed by the addition of asolution of methyl 5-(bromomethyl)-6-chloropyridine-2-carboxylate (3 g,11.34 mmol, 1 equiv) in MeCN (10 mL) dropwise with stirring. Theresulting mixture was stirred for 1 h at room temperature. The solidswere filtered out. The filtrate was concentrated under vacuum. Theresidue was purified by silica gel chromatography (Gradient 0-10%MeOH/CH₂Cl₂) to afford the title compound as a yellow solid (1.5 g, 49%yield). MS: (ES, m/z): 245 [M+H]⁺.

Step-5: Isopropyl2,3,4,5-tetrahydropyrido[3,2-f][1,4]oxazepine-8-carboxylate

Into 20-mL sealed tube, was placed methyl6-chloro-5-(((2-hydroxyethyl)amino) methyl)picolinate (1 g, 4.09 mmol, 1equiv), K₂CO₃ (1.103 g, 7.98 mmol, 2 equiv), isopropanol (10 mL) and CuI(156 mg, 0.82 mmol, 0.2 equiv). The resulting solution was stirredovernight at 110° C. in an oil bath. The reaction was then quenched withwater (10 mL) and extracted with EtOAc (3×10 mL). The combined organiclayers were washed with H₂O (3×10 mL), dried over anhydrous Na₂SO₄,filtered, and concentrated under vacuum. The residue purified by silicagel chromatography (Gradient 0-10% MeOH/CH₂Cl₂) to afford the titlecompound as a green solid (148 mg, 14% yield). MS: (ES, m/z): 237[M+H]⁺.

Step-6: Isopropyl4-(cyclohexanecarbonyl)-2,3,4,5-tetrahydropyrido[3,2-f][1,4]oxazepine-8-carboxylate

Into a 10-mL round-bottom flask, was placed isopropyl2,3,4,5-tetrahydropyrido[3,2-f][1,4]oxazepine-8-carboxylate (38 mg, 0.16mmol, 1 equiv), cyclohexanecarbonyl chloride (24.88 mg, 0.17 mmol, 1.05equiv), CH₂Cl₂ (10 mL) and Et₃N (18 mg, 0.18 mmol, 1.1 equiv). Theresulting mixture was stirred for 2 h at 0° C. The reaction was thenquenched with water (10 mL) and extracted with EtOAc (3×20 mL). Thecombined organic layers were washed with H₂O (3×20 mL), dried overanhydrous Na₂SO₄, filtered, and concentrated under vacuum. The residuepurified by silica gel chromatography (Gradient 0-10% MeOH/CH₂Cl₂) toafford the title compound as a white solid (20 mg, 32% yield). MS: (ES,m/z): 347 [M+H]⁺.

Step-7:4-(Cyclohexanecarbonyl)-N-hydroxy-2,3,4,5-tetrahydropyrido[3,2-f][1,4]oxazepine-8-carboxamide

Into a 8-mL vial, was placed a solution of isopropyl4-(cyclohexanecarbonyl)-2,3,4,5-tetrahydropyrido[3,2-f][1,4]oxazepine-8-carboxylate(18 mg, 0.05 mmol, 1 equiv) in THF/MeOH (2 mL, 4:1), NH₂OH (50% inwater, 604 mg, 9.15 mmol, 176 equiv), aq. 1N NaOH (0.104 mL, 2 equiv).The resulting mixture was stirred for 1 h at room temperature, thencooled to 0° C. and the pH value of the solution was adjusted to 6 with6N HCl. The crude product was purified by Prep-HPLC (Column HSS C18 OBD,1.8 μm, 2.1×50 mm; Mobile Phase A: Water/0.05% TFA; Mobile Phase B:MeCN/0.05% TFA; Flow rate: 0.7 mL/min; Gradient: 5% B to 95% B in 2 min,hold 0.6 min; Detector: UV 254, 220 nm) to afford the title compound asa pink solid (8 mg, 37% yield). ¹H-NMR (300 MHz, DMSO-d₆) δ(ppm): 11.21(s, 1H), 8.96-9.02 (br s, 1H), 8.03-8.05 (d, J=8 Hz, 1H), 7.64-7.62 (d,J=8 Hz, 1H), 7.60-7.66 (dd, J₁=8 Hz, J₂=16 Hz, 1H), 4.80 (s, 1H), 4.65(s, 1H), 4.36-4.39 (d, J=8 Hz, 2H), 3.84-3.94 (d, J=8 HZ, 2H), 2.61-2.67(m, 1H), 1.60-1.65 (m, 4H), 1.04-1.38 (m, 6H). MS: (ES, m/z): 320[M+H]⁺.

Example 60—Preparation ofN-hydroxy-8-(tetrahydro-2H-pyran-4-carbonyl)-6,7,8,9-tetrahydropyrazino[2,3-f][1,4]oxazepine-3-carboxamide

Step-1: 2-(Benzyl((3,5-dichloropyrazin-2-yl)methyl)amino)ethan-1-ol

Into a 500-mL round-bottom flask, was placed3,5-dichloropyrazine-2-carbaldehyde (8 g, 45.20 mmol, 1 equiv),2-(benzylamino)ethan-1-ol (6.85 g, 45.32 mmol, 1 equiv), acetic acid (13mL), and THE (200 mL). The solution was stirred at room temperature for30 min. To this was added sodium triacetoxyborohydride (19.25 g, 2equiv) in portions at 0° C. The resulting solution was stirred overnightat room temperature. The reaction was then quenched with H₂O (50 mL),and extracted with EtOAc (3×50 mL). The combined organic layers werewashed with brine (2×50 mL), dried over anhydrous Na₂SO₄, filtered andconcentrated under vacuum. The residue was purified by silica gelchromatography (EtOAc/pet. ether, 4:1) to afford the title compound as ared oil (6.71 g, 48% yield). MS: (ES, m/z): 312 [M+H]⁺.

Step-2:8-Benzyl-3-chloro-6,7,8,9-tetrahydropyrazino[2,3-f][1,4]oxazepine

Into a 250-mL round-bottom flask, was placed2-(benzyl((3,5-dichloropyrazin-2-yl)methyl)amino)ethan-1-ol (6.7 g,21.46 mmol, 1 equiv) in THF (200 mL). This was followed by the additionof t-BuOK (2.88 g, 1.2 equiv) in portions at 0° C. The resultingsolution was stirred for 3 h at 0° C. in an ice bath. The reaction wasthen quenched H₂O (30 mL), and extracted with EtOAc (3×50 mL). Thecombined organic layers were washed with brine (2×50 mL), dried overanhydrous Na₂SO₄, filtered and concentrated under vacuum. The residuewas purified by silica gel chromatography (EtOAc/pet. ether, 1:3) toafford the title compound as a brown oil (3.2 g, 54% yield). MS: (ES,m/z): 276 [M+H]⁺.

Step-3: Methyl8-benzyl-6,7,8,9-tetrahydropyrazino[2,3-f][1,4]oxazepine-3-carboxylate

Into a 20-mL pressure tank reactor, was placed8-benzyl-3-chloro-6,7,8,9-tetrahydropyrazino[2,3-f][1,4]oxazepine (2 g,7.25 mmol, 1 equiv) in MeOH (10 mL), Et₃N (2.2 g, 21.74 mmol, 3 equiv)and Pd(dppf)Cl₂ (520 mg, 0.71 mmol, 0.1 equiv). To the above CO (g) (30atm) was introduced in. The resulting solution was stirred overnight at90° C. in an oil bath. The resulting mixture was concentrated undervacuum. The residue was purified by silica gel chromatography(EtOAc/pet. ether, 1:2) to afford the title compound as a yellow oil(1.7 g, 78% yield). MS: (ES, m/z): 300 [M+H]⁺.

Step-4: Methyl6,7,8,9-tetrahydropyrazino[2,3-f][1,4]oxazepine-3-carboxylate

Into a 250-mL 3-necked round-bottom flask purged and maintained with aninert atmosphere of nitrogen, was placed methyl8-benzyl-6,7,8,9-tetrahydropyrazino[2,3-f][1,4]oxazepine-3-carboxylate(800 mg, 2.67 mmol, 1 equiv) in 1,2-dichloroethane (30 mL). This wasfollowed by the slow addition of chloro(1-chloroethoxy)methanone (800mg, 5.60 mmol, 2.09 equiv) at 0° C. over 10 min. The resulting solutionwas stirred for 4 h at 80° C. in an oil bath. The mixture wasconcentrated under vacuum. Then to this was added MeOH (50 mL). Theresulting solution was stirred for 1 h at 80° C. in an oil bath. Thesolids were collected by filtration. The crude product was purified byre-crystallization from MeOH to afford the title compound as a whitesolid (500 mg, 89% yield). MS: (ES, m/z): 210 [M+H]⁺.

Step-5: Methyl8-(tetrahydro-2H-pyran-4-carbonyl)-6,7,8,9-tetrahydropyrazino[2,3-f][1,4]oxazepine-3-carboxylate

Into a 8-mL vial, was placed methyl6,7,8,9-tetrahydropyrazino[2,3-f][1,4]oxazepine-3-carboxylate (100 mg,0.48 mmol, 1 equiv), Et₃N (144.8 mg, 1.43 mmol, 2.98 equiv), CH₂C₁₂ (2mL). To this was added oxane-4-carbonyl chloride (141.6 mg) dropwisewith stirring at 0° C. The resulting solution was stirred for 2 h atroom temperature. The resulting mixture was concentrated under vacuum.The residue was purified by silica gel chromatography (EtOAc/pet. ether,1:3) to afford the title compound as a green solid (80 mg, 52% yield).MS: (ES, m/z): 322 [M+H]⁺.

Step-6:N-Hydroxy-8-(tetrahydro-2H-pyran-4-carbonyl)-6,7,8,9-tetrahydropyrazino[2,3-f][1,4]oxazepine-3-carboxamide

Into a 8-mL vial, was placed methyl8-(tetrahydro-2H-pyran-4-carbonyl)-6,7,8,9-tetrahydropyrazino[2,3-f][1,4]oxazepine-3-carboxylate(80 mg, 0.25 mmol, 1 equiv), THF/MeOH (4:1, 1.5 mL), NH₂OH (50% inwater, 1.97 g, 29.85 mmol, 120 equiv), aq. 1N NaOH (0.50 mL, 0.50 mmol,2 equiv). The resulting solution was stirred for 1 h at roomtemperature. The pH value of the solution was adjusted to 6 with 6N HClat 0° C. The crude product was purified by Prep-HPLC (Column: XbridgePrep C18 OBD, 5 μm, 19×50 mm; Mobile Phase A: Water/0.05% formic acid;Mobile Phase B: MeCN; Flow rate: 0.7 mL/min; Gradient: 5% B to 20% B in7 min; Detector, UV 254, 220 nm) to afford the title compound as a whitesolid (34 mg, 38% yield). ¹H-NMR (400 MHz, DMSO-d₆) δ(ppm): 11.45 (br s,1H), 9.19 (br s, 1H), 8.71-8.68 (m, 1H), 5.02 (s, 1H), 4.91 (s, 1H),4.63-4.57 (m, 2H), 4.03-4.00 (m, 1H), 3.93-3.90 (m, 1H), 3.84-3.77 (m,2H), 3.41-3.31 (m, 1H), 3.28-3.25 (m, 1H), 2.99-2.82 (m, 1H), 1.56-1.45(m, 3H), 1.28-1.25 (m, 1H). MS: (ES, m/z): 323 [M+H]⁺.

TABLE 33 The following compound was prepared according to the method ofExample 60. Found Structure M + H ¹H-NMR (400 MHz, DMSO-d₆) δ(ppm)

(ES, m/z): 321 [M + H]⁺ 11.52 (br s, 1H), 8.71-8.67 (d, 1H), 4.97 (s,1H), 4.90 (s, 1H), 4.63-4.56 (m, 2H), 3.99-3.89 (m, 2H), 2.66-2.62 (m,1H), 1.69-1.60 (m, 4H), 1.35-1.11 (m, 6H)

Example 61—Preparation ofN-hydroxy-4-(4-methoxybenzoyl)-2-oxo-2,3,4,5-tetrahydro-1H-benzo[e][1,4]diazepine-7-carboxamide

Step-1: Methyl 3-(((2-methoxy-2-oxoethyl)amino)methyl)-4-nitrobenzoate

Into a 250-mL round-bottom flask that has been purged and maintainedwith an inert atmosphere of nitrogen, were placed methyl 2-aminoacetate(12 g, 135 mmol, 1.5 equiv), methyl 3-(bromomethyl)-4-nitrobenzoate (12g, 26 mmol, 1 equiv), DIEA (32 mL, 3 equiv) and DMF (120 mL). Theresulting solution was stirred for 12 h at room temperature. Thereaction was then quenched by the addition of water. The resultingsolution was extracted with EtOAc (3×100 mL) and the combined organiclayer was washed with brine (100 mL). The organic mixture was dried overanhydrous Na₂SO₄, filtered, and concentrated under vacuum. The residuewas purified by silica gel chromatography (Gradient 1:10 to 1:1EtOAc/hexanes) to afford the title compound as a yellow solid (4.9 g,66% yield). MS: (ES, m/z): 283 [M+H]⁺.

Step-2: Methyl3-(((tert-butoxycarbonyl)(2-methoxy-2-oxoethyl)amino)methyl)-4-nitrobenzoate

Into a 100-mL round-bottom flask, were placed methyl3-(((2-methoxy-2-oxoethyl)amino)methyl)-4-nitrobenzoate (4.7 g, 16.8mmol, 1 equiv), CH₂Cl₂ (100 mL), di-tert-butyl dicarbonate (4.4 g, 20.2mmol, 1.2 equiv) and 4-dimethylaminopyridine (82 mg, 0.67 mmol, 0.04equiv). The resulting solution was stirred for 4 h at room temperature.The resulting mixture was concentrated under vacuum. The residue waspurified by silica gel chromatography (Gradient 1:10 to 1:1EtOAc/petroleum ether) to afford the title compound as a yellow oil (2.8g, 44% yield). MS: (ES, m/z): 283 [M-Boc+H]⁺.

Step-3: Methyl4-amino-3-(((tert-butoxycarbonyl)(2-methoxy-2-oxoethyl)amino)methyl)benzoate

Into a 100-mL round-bottom flask, were placed methyl3-(((tert-butoxycarbonyl)(2-methoxy-2-oxoethyl)amino)methyl)-4-nitrobenzoate(2.8 g, 7.3 mmol, 1 equiv), MeOH (30 mL) and palladium on carbon (280mg). The resulting solution was stirred for 18 h at room temperatureunder a H₂ balloon. The solids were filtered out and the filtrate wasconcentrated under reduced pressure to afford the title compound as abrown oil (1.9 g, 74% yield). MS: (ES, m/z): 253 [M-Boc+H]⁺.

Step-4: 4-(tert-Butyl) 7-methyl2-oxo-1,2,3,5-tetrahydro-4H-benzo[e][1,4]diazepine-4,7-dicarboxylate

Into a 250-mL round-bottom flask that has been purged and maintainedwith an inert atmosphere of nitrogen, were placed methyl4-amino-3-(((tert-butoxycarbonyl)(2-methoxy-2-oxoethyl)amino)methyl)benzoate(1.9 g, 7.5 mmol, 1 equiv), THE (100 mL) and sodium hydride (239 mg, 10mmol, 1.3 equiv). The resulting solution was stirred for 4 h at roomtemperature. The reaction mixture was poured into water/ice andextracted with EtOAc (3×150 mL). The combined organic layers was washedwith brine (100 mL), dried over anhydrous Na₂SO₄, filtered, andconcentrated under vacuum. The crude product was recrystallized fromdiethyl ether to afford the title compound as a white solid (0.5 g, 21%yield). ¹H-NMR (400 MHz, CDCl₃) δ (ppm): 10.34-10.41 (m, 1H), 7.76-7.79(m, 2H), 7.17-7.20 (m, 1H), 4.27-4.53 (m, 4H), 3.82 (s, 3H), 1.34 (s,3H), 1.20 (s, 6H).

Step-5: Methyl2-oxo-2,3,4,5-tetrahydro-1H-benzo[e][1,4]diazepine-7-carboxylate

Into a 500-mL round-bottom flask that has been purged and maintainedwith an inert atmosphere of nitrogen, were placed 4-(tert-butyl)7-methyl2-oxo-1,2,3,5-tetrahydro-4H-benzo[e][1,4]diazepine-4,7-dicarboxylate (12g, 37 mmol, 1 equiv) and 4N HCl in dioxane (360 mL). The resultingsolution was stirred for 6 h at room temperature. The resulting mixturewas concentrated under vacuum and washed with diethyl ether (300 mL) toafford the title compound as the HCl salt as a white solid (9.5 g, 99%yield). MS: (ES, m/z): 221 [M+H]⁺.

Step-6: Methyl4-(4-methoxybenzoyl)-2-oxo-2,3,4,5-tetrahydro-1H-benzo[e][1,4]diazepine-7-carboxylate

To a solution of 4-methoxybenzoic acid (20 mg, 0.136 mmol, 1 equiv) in1,2-dichloroethane (1.4 mL) were added DMC (27.7 mg, 0.164 mmol, 1.2equiv), DIEA (60 μL, 0.341 mmol, 2.5 equiv) and methyl2-oxo-2,3,4,5-tetrahydro-1H-benzo[e][1,4]diazepine-7-carboxylatehydrochloride (35 mg, 0.136 mmol, 1 equiv). The reaction mixture wasstirred at room temperature overnight. The reaction mixture waspartitioned between CH₂Cl₂ and water. The layers were separated. Theorganic layer was washed with brine, and dried over anhydrous Na₂SO₄.The solution was filtered, and concentrated. This crude material waspurified by silica gel chromatography (Gradient 20-80% EtOAc/hexanes) toafford the title compound as a white solid (29.7 mg, 62% yield). MS:(ES, m/z): 355 [M+H]⁺.

Step-7:N-Hydroxy-4-(4-methoxybenzoyl)-2-oxo-2,3,4,5-tetrahydro-1H-benzo[e][1,4]diazepine-7-carboxamide

To a solution of methyl4-(4-methoxybenzoyl)-2-oxo-2,3,4,5-tetrahydro-1H-benzo[e][1,4]diazepine-7-carboxylate(29 mg, 0.082 mmol, 1 equiv) in MeOH/THF (1:4, 1.6 mL) were added NH₂OH(50% in H₂O, 200 μL, 3.27 mmol, 40 equiv) and aq. 2N NaOH (82 μL, 0.164mmol, 2 equiv). The reaction was stirred at room temperature overnight.Additional NH₂OH (50% in H₂O, 90 μL) and aq. 2N NaOH (90 μL) were addedand the reaction was stirred at 30° C. for 2 days. The reaction wasacidified with 2N HCl. The mixture was concentrated and the residue waspurified by Prep-HPLC (Column XBridge RP C18 OBD, 5 μM, 19×50 mm; MobilePhase A: Water/0.1% Formic Acid; Mobile Phase B: MeCN/0.1% Formic Acid;Flow rate: 20 mL/min; Gradient: 5% B to 70% B in 7 min; Detector: UV254, 220 nm) to afford the title compound as a white solid (4.9 mg, 17%yield). ¹H-NMR (300 MHz, DMSO-d₆) δ(ppm): 11.10 (br s, 1H), 10.40 (br s,1H), 9.02 (br s, 1H), 7.76 (br s, 1H), 7.56-7.66 (m, 1H), 7.31 (br d,J=8.8 Hz, 2H), 7.11 (d, J=8.5 Hz, 1H), 6.95 (br d, J=8.8 Hz, 2H), 4.65(s, 2H), 4.28 (br s, 2H), 3.76 (s, 3H). MS: (ES, m/z): 356 [M+H]⁺.

TABLE 34 The following compound was prepared according to the method ofExample 61. Found Structure M + H ¹H-NMR (400 MHz, DMSO-d₆) δ(ppm)

(ES, m/z): 370 [M + H]⁺ 11.15 (br s, 1H), 10.26 (br s, 1H), 9 (br s,1H), 7.70- 7.75 (m, 1H), 7.51-7.65 (m, 1H), 6.94-7.14 (m, 3H), 6.72-6.79(m, 2H), 4.75 (s, 1H), 4.53 (s, 1H), 4.42 (s, 1H), 4.35 (s, 1H), 3.67(s, 3H), 3.58-3.64 (m, 2H)

(ES, m/z): 318 [M + H]⁺

Example 62—Preparation of4-Cyclohexanecarbonyl-N-hydroxy-2-oxo-2,3,4,5-tetrahydro-1H-1,4-benzodiazepine-7-carboxamide

Step-1: Methyl4-(cyclohexanecarbonyl)-2-oxo-2,3,4,5-tetrahydro-1H-benzo[e][1,4]diazepine-7-carboxylate

To a solution of methyl2-oxo-2,3,4,5-tetrahydro-1H-benzo[e][1,4]diazepine-7-carboxylate (62.5mg, 0.284 mmol, 1 equiv) in DMF (1.5 mL) was added cyclohexanecarboxylicacid (38.2 mg, 0.298 mmol, 1.05 equiv), DIEA (149 μL, 0.851 mmol, 3equiv) and HBTU (124 mg, 0.326 mmol, 1.1 equiv). The reaction mixturewas stirred at room temperature for 3 h. Water was added and theprecipitate that formed was collected by filtration to afford the titlecompound (94 mg) which was used without further purification. MS: (ES,m/z): 331 [M+H]⁺.

Step-2:4-Cyclohexanecarbonyl-N-hydroxy-2-oxo-2,3,4,5-tetrahydro-1H-1,4-benzodiazepine-7-carboxamide

To a solution of methyl4-(cyclohexanecarbonyl)-2-oxo-2,3,4,5-tetrahydro-1H-benzo[e][1,4]diazepine-7-carboxylate(94 mg, 0.285 mmol) in MeOH (750 μL) and THE (3 mL) was added NH₂OH (50%in H₂O, 1.48 mL, 24.2 mmol, 85 equiv) and aq. 2N NaOH (285 μL, 0.569mmol, 2 equiv). The reaction was stirred at room temperature for 2 h andwas directly purified by Prep-HPLC (Column XBridge RP C18 OBD, 5 μM,19×50 mm; Mobile Phase A: Water/0.1% Formic Acid; Mobile Phase B:MeCN/0.1% Formic Acid; Flow rate: 20 mL/min; Gradient: 2% B to 50% B in7 min; Detector: UV 254, 220 nm) to afford the title compound (1.7 mg,2% yield over 2 steps). MS: (ES, m/z): 332 [M+H]⁺.

Example 63—Preparation of4-(cyclohexanecarbonyl)-N-hydroxy-2,3,4,5-tetrahydrobenzo[f][1,4]oxazepine-8-carboxamide

Step-1: Methyl4-(cyclohexanecarbonyl)-2,3,4,5-tetrahydrobenzo[f][1,4]oxazepine-8-carboxylate

A 2 mL reaction vial was charged with methyl2,3,4,5-tetrahydrobenzo[f][1,4]oxazepine-8-carboxylate (0.2M in1,2-dichloroethane, 150 μL, 30 μmol) and cyclohexanecarboxylic acid(0.2M in N,N-dimethylacetamide/10% Et₃N, 165 μL, 33 μmol). A solution ofDMC (0.2M in 1,2-dichloroethane, 165 μL, 33 μmol) was added and the vialwas sealed and shaken at room temperature overnight. The reactionmixture was diluted with brine (500 μL) and extracted with EtOAc (2×600μL). The combined organic layers were evaporated to dryness underreduced pressure.

Step-2:4-(Cyclohexanecarbonyl)-N-hydroxy-2,3,4,5-tetrahydrobenzo[f][1,4]oxazepine-8-carboxamide

Mixed solvent of THF/MeOH (3:1, 180 μL) was added to the vial of methyl4-(cyclohexanecarbonyl)-2,3,4,5-tetrahydrobenzo[f][1,4]oxazepine-8-carboxylateand it was shaken at 50° C. for 15 min to dissolve the residue. NH₂OH(50% in water, 125 μL) was added followed by aq. 1N NaOH (85 μL) and thevial was sealed and shaken at room temperature overnight. The solventwas evaporated under reduce pressure and the residue was dissolved inDMSO (500 L) then purified by HPLC to yield the title compound (1.9 mg,30% o yield). MS: (ES, m/z): 319 [M+H]⁺.

TABLE 35 The following compounds were prepared by the parallel synthesismethod of Example 63. Structure Found M + H (ES)

343

343

357

357

381

357

352

353

373

343

379

405

355

373

344

321

353

398

277

291

333

355

409

339

305

341

341

341

396

398

395

419

377

333

305

279

412

348

384

336

357

359

353

355

357

362

370

353

412

323

355

358

305

327

291

281

293

295

411

385

379

361

415

431

359

405

385

356

373

413

361

447

409

395

427

385

426

425

399

393

371

419

424

355

427

369

349

321

354

397

342

386

341

291

335

357

321

355

348

319

421

421

307

421

367

367

321

417

371

387

383

387

387

383

354

355

369

357

359

293

307

333

309

345

279

291

319

293

323

323

337

Example 64—Preparation of methyl2,3,4,5-tetrahydrobenzo[f][1,4]oxazepine-7-carboxylate

Step-1: Methyl 4-bromo-3-(bromomethyl)benzoate

Methyl 4-bromo-3-methylbenzoate (11.4 g, 0.05 mol) was added to carbontetrachloride (80 mL) in a 250 mL 3-three neck round-bottomed flask. Tothe resulting solution were added successively and in single portions,N-bromosuccinimide (9.3 g, 0.053 mol) and dibenzoylperoxide (0.6 g, 5mol %). The resulting suspension was then heated to reflux for 4 h. Uponcooling to ambient temperature, the reaction mixture was filtered, andthe filter cake washed with a few portions of carbon tetrachloride. Thefiltrate was then removed under reduced pressure, and the resultingsemi-solid was partitioned between EtOAc and an aqueous %/2 saturatedsodium carbonate solution. The organic layer was washed with water andbrine, and then dried over magnesium sulfate. The solution was filteredand solvent was removed under reduced pressure, providing 15.5 g of anoff-white solid, which was purified by silica gel chromatography (0% to6% EtOAc/hexanes) to afford the title compound (9.5 g, 61% yield).

Step-2: Methyl 4-bromo-3-(((2-hydroxyethyl)amino)methyl)benzoate

Ethanolamine (7.7 mL, 0.125 mol) was added to acetonitrile (80 mL) in a500 mL 3-neck round-bottomed flask. To the resulting clear solution wasadded powdered potassium carbonate (3.5 g, 0.025 mol) in a singleportion, washing in with more acetonitrile (10 mL). The resultingsuspension was cooled in an ice-acetone bath. With the help of anultrasonic bath, methyl 4-bromo-3-(bromomethyl)benzoate (7.7 g, 0.025mol) was dissolved in acetonitrile (100 mL), and transferred to anaddition funnel. This solution was added over 1 h to the stirringsuspension, temperature remaining below 0° C. throughout. After theaddition was complete, the reaction mixture was stirred for 3 h at icetemperature, before being allowed to warm to 10° C. The entire reactionmixture was evaporated, and the resulting residue partitioned betweenEtOAc and water. The organic layer was washed with water three times,and then once with brine. After drying over magnesium sulfate andfiltering, solvent was removed under reduced pressure to obtain a clearoil, which solidified upon standing. This was placed under high vacuumto obtain the title compound (5.8 g, 80% yield), which was used withoutfurther purification.

Step-3: Methyl 2,3,4,5-tetrahydrobenzo[f][1,4]oxazepine-7-carboxylate

Methyl 4-bromo-3-(((2-hydroxyethyl)amino)methyl)benzoate (1.0 g, 0.0035mol), potassium carbonate (1.0 g, 0.007 mol), and copper (I) iodide(0.13 g, 20 mol %) were placed into a 80 mL microwave tube along with amagnetic stir bar. Previously degassed 2-propanol (25 mL) was added, andthe resulting suspension heated at 125° C. for 2.5 h. This process wasrepeated twice more. The three reactions were combined, the suspensionwas filtered, and the filter cake washed with more 2-propanol. Thefiltrate was pre-absorbed directly onto silica gel and was which waspurified by silica gel chromatography (0% to 10% EtOH+5% NH₄OH/CH₂Cl₂)to afford a greenish oil (1.4 g). This material was further purified bysilica gel chromatography (60% to 100% EtOAc+5% Et₃N/hexanes) to affordthe title compound as an amber oil (1.0 g, 46% yield). ¹H-NMR (300 MHz,CDCl₃) δ (ppm): 7.81-7.87 (m, 2H), 7.00-7.06 (m, 1H), 4.05-4.11 (m, 2H),3.99 (s, 2H), 3.87 (s, 3H), 3.20-3.26 (m, 2H). MS: (APCI, m/z): 208[M+H]⁺.

Example 65—In Vitro Histone Deacetylase Assay

The enzymatic HDAC6 assay was performed using electrophoretic mobilityshift assay. Full length human recombinant HDAC6 protein was expressedin baculoviral system and purified by affinity chromatography. Theenzymatic reactions were assembled in 384 well plates in a total volumeof 25 μL in a reaction buffer composing: 100 mM HEPES, pH7.5, 25 mM KCl,0.1% bovine serum albumin, 0.01% Triton X-100, 1% DMSO (from compounds)2 μM of the fluorescently labeled peptide substrate and enzyme. Theenzyme was added at a final concentration of 1 nM. The peptide substrateRHKK(Ac)—NH2 was used. The compounds were tested at 12 concentrationsspaced by 3× dilution intervals. Negative control samples(100%-inhibition in the absence of inhibitor) and positive controlsamples (100%-inhibition) were assembled in replicates of four in eachassay plate. The reactions were incubated at 25° C. and quenched by theaddition of 45 μL of termination buffer (100 mM HEPES, pH 7.5, 0.01%Triton X-100, 0.05% SDS).

The terminated assay plates were analyzed on LabChip® 3000 microfluidicelectrophoresis instrument (Perkin Elmer/Caliper Life Sciences). Thefluorescence intensity of the electrophoretically separatedde-acetylated product and substrate peptide was measured. Activity ineach sample was determined as the product to sum ratio (PSR): P/(S+P),where P is the peak height of the product peptide and S is the peakheight of the substrate peptide. Percent inhibition (P_(inh)) isdetermined using the following equation:

P_(inh)=(PSR_(0%)−PSR_(inh))/(PSR_(0%)−PSR_(100%))*100, where PSR_(inh)is the product sum ratio in the presence of inhibitor, PSR_(0%) is theaverage product sum ration in the absence of inhibitor and PSR_(100%) isthe average product sum ratio in 100%-inhibition control samples. TheIC₅₀ values of inhibitors were determined by fitting the %-inhibitioncurves with 4 parameter dose-response model using XLfit 4 software.

As set forth in Table 36, below, IC₅₀ values are defined as follows:IC50≤0.1 μM (+++); IC50>0.1 μM and ≤0.5 μM (++); IC50>0.5 μM (+).

TABLE 36 Inhibitory Concentration (IC₅₀) Values for RepresentativeCompounds against HDAC6. ChemDraw IUPAC Name Activity Range4-(2,2-dimethyltetrahydro-2H-pyran-4-carbonyl)-N-hydroxy- ++2,3,4,5-tetrahydrobenzo[f][1,4]oxazepine-8-carboxamideN-hydroxy-4-(2-methyl-2-(pyridin-2-yl)propanoyl)-2,3,4,5- ++tetrahydrobenzo[f][1,4]oxazepine-8-carboxamide4-(2,6-dimethylbenzoyl)-N-hydroxy-2,3,4,5- ++tetrahydrobenzo[f][1,4]oxazepine-8-carboxamideN-hydroxy-4-(3-methoxy-2,2-dimethylpropanoyl)-2,3,4,5- +++tetrahydrobenzo[f][1,4]oxazepine-8-carboxamide4-(8-oxabicyclo[3.2.1]octane-3-carbonyl)-N-hydroxy-2,3,4,5- +++tetrahydrobenzo[f][1,4]oxazepine-8-carboxamideN-hydroxy-4-(3-(propylamino)benzo[b]thiophene-2-carbonyl)- +++2,3,4,5-tetrahydrobenzo[f][1,4]oxazepine-8-carboxamide4-(3-(dimethylamino)benzo[b]thiophene-2-carbonyl)-N-hydroxy- +++2,3,4,5-tetrahydrobenzo[f][1,4]oxazepine-8-carboxamide tert-butyl7-(8-(hydroxycarbamoyl)-2,3,4,5- ++tetrahydrobenzo[f][1,4]oxazepine-4-carbonyl)-5-oxa-2-azaspiro[3.4]octane-2-carboxylate tert-butyl7-(8-(hydroxycarbamoyl)-2,3,4,5- ++tetrahydrobenzo[f][1,4]oxazepine-4-carbonyl)-5-thia-2-azaspiro[3.4]octane-2-carboxylate 5,5-dioxide(S)-N-hydroxy-4-(tetrahydro-2H-pyran-3-carbonyl)-2,3,4,5- +++tetrahydrobenzo[f][1,4]oxazepine-8-carboxamide(R)-N-hydroxy-4-(tetrahydro-2H-pyran-3-carbonyl)-2,3,4,5- +++tetrahydrobenzo[f][1,4]oxazepine-8-carboxamide(R)-N-hydroxy-4-(tetrahydrofuran-3-carbonyl)-2,3,4,5- +++tetrahydrobenzo[f][1,4]oxazepine-8-carboxamide(S)-N-hydroxy-4-(tetrahydrofuran-3-carbonyl)-2,3,4,5- +++tetrahydrobenzo[f][1,4]oxazepine-8-carboxamide4-benzoyl-N-hydroxy-2,3,4,5-tetrahydrobenzo[f][1,4]oxazepine-8- +++carboxamideN-hydroxy-4-pivaloyl-2,3,4,5-tetrahydrobenzo[f][1,4]oxazepine-8- +++carboxamide4-acetyl-N-hydroxy-2,3,4,5-tetrahydrobenzo[f][1,4]oxazepine-8- +++carboxamide4-formyl-N-hydroxy-2,3,4,5-tetrahydrobenzo[f][1,4]oxazepine-8- +++carboxamide tert-butyl 3-(8-(hydroxycarbamoyl)-2,3,4,5- ++tetrahydrobenzo[f][1,4]oxazepine-4-carbonyl)-3H-spiro[isobenzofuran-1,4′-piperidine]-1′-carboxylateN-hydroxy-4-(8-azaspiro[4.5]decane-2-carbonyl)-2,3,4,5- +++tetrahydrobenzo[f][1,4]oxazepine-8-carboxamide tert-butyl8-(8-(hydroxycarbamoyl)-2,3,4,5- +++tetrahydrobenzo[f][1,4]oxazepine-4-carbonyl)-2-azaspiro[4.5]decane-2-carboxylateN-hydroxy-4-(2-azaspiro[4.5]decane-8-carbonyl)-2,3,4,5- +++tetrahydrobenzo[f][1,4]oxazepine-8-carboxamide tert-butyl6-(8-(hydroxycarbamoyl)-2,3,4,5- ++tetrahydrobenzo[f][1,4]oxazepine-4-carbonyl)-2-azaspiro[4.4]nonane-2-carboxylateN-hydroxy-4-(2-azaspiro[4.4]nonane-6-carbonyl)-2,3,4,5- ++tetrahydrobenzo[f][1,4]oxazepine-8-carboxamideN-hydroxy-4-(3H-spiro[isobenzofuran-1,4′-piperidine]-3-carbonyl)- ++2,3,4,5-tetrahydrobenzo[f][1,4]oxazepine-8-carboxamide tert-butyl2-(8-(hydroxycarbamoyl)-2,3,4,5- ++tetrahydrobenzo[f][1,4]oxazepine-4-carbonyl)-2H-spiro[benzofuran-3,4′-piperidine]-1′-carboxylateN-hydroxy-4-(2H-spiro[benzofuran-3,4′-piperidine]-2-carbonyl)- ++2,3,4,5-tetrahydrobenzo[f][1,4]oxazepine-8-carboxamide tert-butyl3-(8-(hydroxycarbamoyl)-2,3,4,5- ++tetrahydrobenzo[f][1,4]oxazepine-4-carbonyl)-2,3-dihydrospiro[indene-1,4′-piperidine]-1′-carboxylate4-(2,3-dihydrospiro[indene-1,4′-piperidine]-3-carbonyl)-N-hydroxy- ++2,3,4,5-tetrahydrobenzo[f][1,4]oxazepine-8-carboxamide tert-butyl9-(8-(hydroxycarbamoyl)-2,3,4,5- ++tetrahydrobenzo[f][1,4]oxazepine-4-carbonyl)-3-azaspiro[5.5]undecane-3-carboxylate tert-butyl2-(8-(hydroxycarbamoyl)-2,3,4,5- ++tetrahydrobenzo[f][1,4]oxazepine-4-carbonyl)-8-azaspiro[4.5]decane-8-carboxylateN-hydroxy-4-(3-azaspiro[5.5]undecane-9-carbonyl)-2,3,4,5- +++tetrahydrobenzo[f][1,4]oxazepine-8-carboxamideN-hydroxy-4-(5-azaspiro[2.5]octane-1-carbonyl)-2,3,4,5- +tetrahydrobenzo[f][1,4]oxazepine-8-carboxamideN-hydroxy-4-(5-azaspiro[2.4]heptane-1-carbonyl)-2,3,4,5- +tetrahydrobenzo[f][1,4]oxazepine-8-carboxamideN-hydroxy-4-(6-azaspiro[2.5]octane-1-carbonyl)-2,3,4,5- ++tetrahydrobenzo[f][1,4]oxazepine-8-carboxamide tert-butyl1-(8-(hydroxycarbamoyl)-2,3,4,5- ++tetrahydrobenzo[f][1,4]oxazepine-4-carbonyl)-6-azaspiro[2.5]octane-6-carboxylate(R)-N-hydroxy-2-methyl-4-(1-methylcyclobutane-1-carbonyl)- +++2,3,4,5-tetrahydrobenzo[f][1,4]oxazepine-8-carboxamide(R)-4-formyl-N-hydroxy-2-methyl-2,3,4,5- +++tetrahydrobenzo[f][1,4]oxazepine-8-carboxamide(R)-4-acetyl-N-hydroxy-2-methyl-2,3,4,5- +tetrahydrobenzo[f][1,4]oxazepine-8-carboxamide(S)-4-acetyl-N-hydroxy-2-methyl-2,3,4,5- +tetrahydrobenzo[f][1,4]oxazepine-8-carboxamide(S)-N-hydroxy-2-methyl-4-(1-methylcyclobutane-1-carbonyl)- ++2,3,4,5-tetrahydrobenzo[f][1,4]oxazepine-8-carboxamide(S)-4-formyl-N-hydroxy-2-methyl-2,3,4,5- +++tetrahydrobenzo[f][1,4]oxazepine-8-carboxamideN-hydroxy-3,3-dimethyl-4-(1-methylcyclobutane-1-carbonyl)- +2,3,4,5-tetrahydrobenzo[f][1,4]oxazepine-8-carboxamide4-acetyl-N-hydroxy-3,3-dimethyl-2,3,4,5- ++tetrahydrobenzo[f][1,4]oxazepine-8-carboxamide(R)-4-acetyl-N-hydroxy-3-isopropyl-2,3,4,5- ++tetrahydrobenzo[f][1,4]oxazepine-8-carboxamide(R)-N-hydroxy-3-isopropyl-4-(1-methylcyclobutane-1-carbonyl)- +2,3,4,5-tetrahydrobenzo[f][1,4]oxazepine-8-carboxamide(S)-4-acetyl-N-hydroxy-3-isopropyl-2,3,4,5- ++tetrahydrobenzo[f][1,4]oxazepine-8-carboxamide(S)-N-hydroxy-3-isopropyl-4-(1-methylcyclobutane-1-carbonyl)- +++2,3,4,5-tetrahydrobenzo[f][1,4]oxazepine-8-carboxamide(R)-4-formyl-N-hydroxy-3-methyl-2,3,4,5- +++tetrahydrobenzo[f][1,4]oxazepine-8-carboxamide(R)-N-hydroxy-3-methyl-4-(1-methylcyclobutane-1-carbonyl)- ++2,3,4,5-tetrahydrobenzo[f][1,4]oxazepine-8-carboxamide(R)-4-acetyl-N-hydroxy-3-methyl-2,3,4,5- +tetrahydrobenzo[f][1,4]oxazepine-8-carboxamide(S)-N-hydroxy-3-methyl-4-(1-methylcyclobutane-1-carbonyl)- +++2,3,4,5-tetrahydrobenzo[f][1,4]oxazepine-8-carboxamide(S)-4-(1,1-dioxidotetrahydro-2H-thiopyran-4-carbonyl)-N-hydroxy- +++3-methyl-2,3,4,5-tetrahydrobenzo[f][1,4]oxazepine-8-carboxamide(S)-N-hydroxy-4-(1-methoxycyclopentane-1-carbonyl)-3-methyl- +++2,3,4,5-tetrahydrobenzo[f][1,4]oxazepine-8-carboxamide(3S)-4-(1,1-dioxidotetrahydrothiophene-3-carbonyl)-N-hydroxy-3- +++methyl-2,3,4,5-tetrahydrobenzo[f][1,4]oxazepine-8-carboxamide(S)-N-hydroxy-4-(1-methoxycyclobutane-1-carbonyl)-3-methyl- +++2,3,4,5-tetrahydrobenzo[f][1,4]oxazepine-8-carboxamide(S)-N-hydroxy-3-methyl-4-(3-methyloxetane-3-carbonyl)-2,3,4,5- +++tetrahydrobenzo[f][1,4]oxazepine-8-carboxamide(S)-N-hydroxy-3-methyl-4-(oxetane-3-carbonyl)-2,3,4,5- +++tetrahydrobenzo[f][1,4]oxazepine-8-carboxamide(S)-4-(1,1-dioxidothietane-3-carbonyl)-N-hydroxy-3-methyl-2,3,4,5- +++tetrahydrobenzo[f][1,4]oxazepine-8-carboxamide(S)-N-hydroxy-4-(1-methoxycyclopropane-1-carbonyl)-3-methyl- +++2,3,4,5-tetrahydrobenzo[f][1,4]oxazepine-8-carboxamide(S)-N-hydroxy-3-methyl-4-(tetrahydro-2H-pyran-4-carbonyl)- +++2,3,4,5-tetrahydrobenzo[f][1,4]oxazepine-8-carboxamide(S)-N-hydroxy-4-(2-methoxy-2-methylpropanoyl)-3-methyl-2,3,4,5- +++tetrahydrobenzo[f][1,4]oxazepine-8-carboxamide(S)-N-hydroxy-3-methyl-4-(4-methyltetrahydro-2H-pyran-4- +++carbonyl)-2,3,4,5-tetrahydrobenzo[f][1,4]oxazepine-8-carboxamide(S)-N-hydroxy-4-(4-methoxytetrahydro-2H-pyran-4-carbonyl)-3- +++methyl-2,3,4,5-tetrahydrobenzo[f][1,4]oxazepine-8-carboxamide(S)-N-hydroxy-4-(1-methoxycyclohexane-1-carbonyl)-3-methyl- +++2,3,4,5-tetrahydrobenzo[f][1,4]oxazepine-8-carboxamide(3S)-4-(8-oxabicyclo[3.2.1]octane-3-carbonyl)-N-hydroxy-3- +++methyl-2,3,4,5-tetrahydrobenzo[f][1,4]oxazepine-8-carboxamide(3S)-4-(2,6-dimethyltetrahydro-2H-pyran-4-carbonyl)-N-hydroxy-3- +++methyl-2,3,4,5-tetrahydrobenzo[f][1,4]oxazepine-8-carboxamide(S)-4-formyl-N-hydroxy-3-methyl-2,3,4,5- +++tetrahydrobenzo[f][1,4]oxazepine-8-carboxamide(S)-4-acetyl-N-hydroxy-3-methyl-2,3,4,5- ++tetrahydrobenzo[f][1,4]oxazepine-8-carboxamide(S)-4-(1-acetylpiperidine-4-carbonyl)-N-hydroxy-3-methyl-2,3,4,5- +++tetrahydrobenzo[f][1,4]oxazepine-8-carboxamide(3S)-4-(1-acetylpyrrolidine-3-carbonyl)-N-hydroxy-3-methyl- +++2,3,4,5-tetrahydrobenzo[f][1,4]oxazepine-8-carboxamide(R)-N-hydroxy-5-methyl-4-(1-methylcyclobutane-1-carbonyl)- +++2,3,4,5-tetrahydrobenzo[f][1,4]oxazepine-7-carboxamide(S)-N-hydroxy-5-methyl-4-(1-methylcyclobutane-1-carbonyl)- ++2,3,4,5-tetrahydrobenzo[f][1,4]oxazepine-7-carboxamide(R)-N-hydroxy-5-methyl-4-(tetrahydro-2H-pyran-4-carbonyl)- +++2,3,4,5-tetrahydrobenzo[f][1,4]oxazepine-7-carboxamide(S)-N-hydroxy-5-methyl-4-(tetrahydro-2H-pyran-4-carbonyl)- +2,3,4,5-tetrahydrobenzo[f][1,4]oxazepine-7-carboxamide4-(cyclohexanecarbonyl)-N-hydroxy-2,3,4,5-tetrahydropyrido[2,3- ++f][1,4]oxazepine-8-carboxamide4-(cyclohexanecarbonyl)-N-hydroxy-2,3,4,5-tetrahydropyrido[3,2- ++f][1,4]oxazepine-8-carboxamideN-hydroxy-4-(2-(4-methoxyphenyl)acetyl)-2-oxo-2,3,4,5- +tetrahydro-1H-benzo[e][1,4]diazepine-7-carboxamideN-hydroxy-4-(4-methoxybenzoyl)-2-oxo-2,3,4,5-tetrahydro-1H- +benzo[e][1,4]diazepine-7-carboxamide4-(cyclohexanecarbonyl)-N-hydroxy-2-oxo-2,3,4,5-tetrahydro-1H- +benzo[e][1,4]diazepine-7-carboxamide4-(cyclohexanecarbonyl)-N-hydroxy-2,3,4,5- +++tetrahydrobenzo[f][1,4]oxazepine-8-carboxamideN-hydroxy-4-(4-methoxybenzoyl)-2,3,4,5- +++tetrahydrobenzo[f][1,4]oxazepine-8-carboxamideN-hydroxy-4-(4-methoxybenzoyl)-2,3,4,5- +tetrahydrobenzo[f][1,4]oxazepine-7-carboxamideN-hydroxy-4-(2-(4-methoxyphenyl)acetyl)-2,3,4,5- +tetrahydrobenzo[f][1,4]oxazepine-8-carboxamideN-hydroxy-4-(2-(4-methoxyphenyl)acetyl)-2,3,4,5- +tetrahydrobenzo[f][1,4]oxazepine-7-carboxamideN-hydroxy-4-(4-(trifluoromethyl)benzoyl)-2,3,4,5- ++tetrahydrobenzo[f][1,4]oxazepine-8-carboxamide4-(benzo[d][1,3]dioxole-5-carbonyl)-N-hydroxy-2,3,4,5- +++tetrahydrobenzo[f][1,4]oxazepine-8-carboxamideN-hydroxy-4-(1H-indole-5-carbonyl)-2,3,4,5- +++tetrahydrobenzo[f][1,4]oxazepine-8-carboxamideN-hydroxy-4-(1-phenylcyclopropane-1-carbonyl)-2,3,4,5- +++tetrahydrobenzo[f][1,4]oxazepine-8-carboxamideN-hydroxy-4-(2-(4-methoxyphenoxy)acetyl)-2,3,4,5- +++tetrahydrobenzo[f][1,4]oxazepine-8-carboxamideN-hydroxy-4-(3-methoxybenzoyl)-2,3,4,5- ++tetrahydrobenzo[f][1,4]oxazepine-8-carboxamide4-(4-(difluoromethoxy)benzoyl)-N-hydroxy-2,3,4,5- ++tetrahydrobenzo[f][1,4]oxazepine-8-carboxamideN-hydroxy-4-(4-phenoxybenzoyl)-2,3,4,5- +++tetrahydrobenzo[f][1,4]oxazepine-8-carboxamide4-(2,3-dihydrobenzofuran-5-carbonyl)-N-hydroxy-2,3,4,5- ++tetrahydrobenzo[f][1,4]oxazepine-8-carboxamide4-(2,4-dimethoxybenzoyl)-N-hydroxy-2,3,4,5- ++tetrahydrobenzo[f][1,4]oxazepine-8-carboxamideN-hydroxy-4-(1-methyl-6-oxo-1,6-dihydropyridine-3-carbonyl)- +2,3,4,5-tetrahydrobenzo[f][1,4]oxazepine-8-carboxamideN-hydroxy-4-(tetrahydro-2H-pyran-4-carbonyl)-2,3,4,5- +++tetrahydrobenzo[f][1,4]oxazepine-8-carboxamide4-(benzofuran-5-carbonyl)-N-hydroxy-2,3,4,5- ++tetrahydrobenzo[f][1,4]oxazepine-8-carboxamideN-hydroxy-4-(4-morpholinobenzoyl)-2,3,4,5- ++tetrahydrobenzo[f][1,4]oxazepine-8-carboxamide4-(cyclopropanecarbonyl)-N-hydroxy-2,3,4,5- ++tetrahydrobenzo[f][1,4]oxazepine-8-carboxamide4-(cyclobutanecarbonyl)-N-hydroxy-2,3,4,5- +++tetrahydrobenzo[f][1,4]oxazepine-8-carboxamideN-hydroxy-4-(1-methylcyclohexane-1-carbonyl)-2,3,4,5- +++tetrahydrobenzo[f][1,4]oxazepine-8-carboxamideN-hydroxy-4-(2-phenylbutanoyl)-2,3,4,5- ++tetrahydrobenzo[f][1,4]oxazepine-8-carboxamide4-(2-cyclohexyl-2-phenylacetyl)-N-hydroxy-2,3,4,5- +tetrahydrobenzo[f][1,4]oxazepine-8-carboxamide4-(bicyclo[4.2.0]octa-1(6),2,4-triene-7-carbonyl)-N-hydroxy- +++2,3,4,5-tetrahydrobenzo[f][1,4]oxazepine-8-carboxamideN-hydroxy-4-(1-methylcyclobutane-1-carbonyl)-2,3,4,5- +++tetrahydrobenzo[f][1,4]oxazepine-8-carboxamide(S)-N-hydroxy-4-(2-phenylpropanoyl)-2,3,4,5- ++tetrahydrobenzo[f][1,4]oxazepine-8-carboxamide(R)-N-hydroxy-4-(2-phenylpropanoyl)-2,3,4,5- +tetrahydrobenzo[f][1,4]oxazepine-8-carboxamideN-hydroxy-4-(3-phenylpropanoyl)-2,3,4,5- +++tetrahydrobenzo[f][1,4]oxazepine-8-carboxamideN-hydroxy-4-(2-(5-methoxy-1H-indol-3-yl)acetyl)-2,3,4,5- +tetrahydrobenzo[f][1,4]oxazepine-8-carboxamide4-(2-(1,1-dioxidothiomorpholino)propanoyl)-N-hydroxy-2,3,4,5- +tetrahydrobenzo[f][1,4]oxazepine-8-carboxamideN-hydroxy-4-(2-(4-(trifluoromethyl)phenyl)acetyl)-2,3,4,5- +tetrahydrobenzo[f][1,4]oxazepine-8-carboxamideN-hydroxy-4-(2-(2-phenoxyphenyl)acetyl)-2,3,4,5- +tetrahydrobenzo[f][1,4]oxazepine-8-carboxamide4-(2-(3-chlorophenoxy)acetyl)-N-hydroxy-2,3,4,5- ++tetrahydrobenzo[f][1,4]oxazepine-8-carboxamideN-hydroxy-4-(4,4,4-trifluorobutanoyl)-2,3,4,5- ++tetrahydrobenzo[f][1,4]oxazepine-8-carboxamide4-(cyclopentanecarbonyl)-N-hydroxy-2,3,4,5- +++tetrahydrobenzo[f][1,4]oxazepine-8-carboxamideN-hydroxy-4-isobutyryl-2,3,4,5-tetrahydrobenzo[f][1,4]oxazepine-8- +++carboxamideN-hydroxy-4-(2-(1-(methylsulfonyl)piperidin-4-yl)acetyl)-2,3,4,5- +tetrahydrobenzo[f][1,4]oxazepine-8-carboxamideN-hydroxy-4-(2-(2-methylthiazol-4-yl)acetyl)-2,3,4,5- ++tetrahydrobenzo[f][1,4]oxazepine-8-carboxamide4-(2-(1,1-dioxidothiomorpholino)acetyl)-N-hydroxy-2,3,4,5- +tetrahydrobenzo[f][1,4]oxazepine-8-carboxamideN-hydroxy-4-(2-morpholinoacetyl)-2,3,4,5- +tetrahydrobenzo[f][1,4]oxazepine-8-carboxamideN-hydroxy-4-(2-methoxy-2-phenylacetyl)-2,3,4,5- ++tetrahydrobenzo[f][1,4]oxazepine-8-carboxamide4-(2-(4-fluorophenyl)propanoyl)-N-hydroxy-2,3,4,5- ++tetrahydrobenzo[f][1,4]oxazepine-8-carboxamide4-(2,3-dihydro-1H-indene-2-carbonyl)-N-hydroxy-2,3,4,5- +++tetrahydrobenzo[f][1,4]oxazepine-8-carboxamideN-hydroxy-4-(3-phenylbutanoyl)-2,3,4,5- ++tetrahydrobenzo[f][1,4]oxazepine-8-carboxamideN-hydroxy-4-(2-phenoxypropanoyl)-2,3,4,5- ++tetrahydrobenzo[f][1,4]oxazepine-8-carboxamide4-(1-acetylpiperidine-3-carbonyl)-N-hydroxy-2,3,4,5- +++tetrahydrobenzo[f][1,4]oxazepine-8-carboxamideN-hydroxy-4-(2-phenoxybutanoyl)-2,3,4,5- ++tetrahydrobenzo[f][1,4]oxazepine-8-carboxamideN-hydroxy-4-(2-phenylcyclopropane-1-carbonyl)-2,3,4,5- +++tetrahydrobenzo[f][1,4]oxazepine-8-carboxamideN-hydroxy-4-(2-(2-oxo-3-(trifluoromethyl)pyridin-1(2H)-yl)acetyl)- ++2,3,4,5-tetrahydrobenzo[f][1,4]oxazepine-8-carboxamideN-hydroxy-4-(2-isobutoxyacetyl)-2,3,4,5- +tetrahydrobenzo[f][1,4]oxazepine-8-carboxamide4-(4,4-difluorocyclohexane-1-carbonyl)-N-hydroxy-2,3,4,5- ++tetrahydrobenzo[f][1,4]oxazepine-8-carboxamideN-hydroxy-4-(N-methyl-N-(methylsulfonyl)glycyl)-2,3,4,5- ++tetrahydrobenzo[f][1,4]oxazepine-8-carboxamide(S)-4-(2,2-dimethylcyclopropane-1-carbonyl)-N-hydroxy-2,3,4,5- ++tetrahydrobenzo[f][1,4]oxazepine-8-carboxamide4-(3,3-difluorocyclobutane-1-carbonyl)-N-hydroxy-2,3,4,5- ++tetrahydrobenzo[f][1,4]oxazepine-8-carboxamide4-(2-cyclopropylacetyl)-N-hydroxy-2,3,4,5- +++tetrahydrobenzo[f][1,4]oxazepine-8-carboxamideN-hydroxy-4-(3-hydroxypropanoyl)-2,3,4,5- +tetrahydrobenzo[f][1,4]oxazepine-8-carboxamideN-hydroxy-4-(1-hydroxycyclopropane-1-carbonyl)-2,3,4,5- +tetrahydrobenzo[f][1,4]oxazepine-8-carboxamideN-hydroxy-4-(2-hydroxy-2-methylpropanoyl)-2,3,4,5- ++tetrahydrobenzo[f][1,4]oxazepine-8-carboxamide4-(2-cyclopentyl-2-hydroxy-2-phenylacetyl)-N-hydroxy-2,3,4,5- +tetrahydrobenzo[f][1,4]oxazepine-8-carboxamideN-hydroxy-4-(2-(3-methoxyphenyl)-2-methylpropanoyl)-2,3,4,5- ++tetrahydrobenzo[f][1,4]oxazepine-8-carboxamide4-(2-(4-chloro-1H-pyrazol-1-yl)-2-methylpropanoyl)-N-hydroxy- +++2,3,4,5-tetrahydrobenzo[f][1,4]oxazepine-8-carboxamide4-(2-cyclohexyl-2-methylpropanoyl)-N-hydroxy-2,3,4,5- ++tetrahydrobenzo[f][1,4]oxazepine-8-carboxamide4-(2-(3,4-dimethoxyphenyl)-2-methylpropanoyl)-N-hydroxy- ++2,3,4,5-tetrahydrobenzo[f][1,4]oxazepine-8-carboxamide4-(2-([1,1′-biphenyl]-4-yl)-2-methylpropanoyl)-N-hydroxy-2,3,4,5- ++tetrahydrobenzo[f][1,4]oxazepine-8-carboxamideN-hydroxy-4-(2-methyl-2-(3-methyl-1H-pyrazol-1-yl)propanoyl)- +++2,3,4,5-tetrahydrobenzo[f][1,4]oxazepine-8-carboxamideN-hydroxy-4-(2-methyl-2-(naphthalen-2-yl)propanoyl)-2,3,4,5- ++tetrahydrobenzo[f][1,4]oxazepine-8-carboxamideN-hydroxy-4-(2-(2-methoxyphenyl)-2-methylpropanoyl)-2,3,4,5- +tetrahydrobenzo[f][1,4]oxazepine-8-carboxamideN-hydroxy-4-(2-methyl-2-(pyridin-3-yl)propanoyl)-2,3,4,5- ++tetrahydrobenzo[f][1,4]oxazepine-8-carboxamide4-(2-(4-fluorophenyl)-2-methylpropanoyl)-N-hydroxy-2,3,4,5- ++tetrahydrobenzo[f][1,4]oxazepine-8-carboxamide4-(2-(2,3-dihydrobenzo[b][1,4]dioxin-6-yl)-2-methylpropanoyl)-N- ++hydroxy-2,3,4,5-tetrahydrobenzo[f][1,4]oxazepine-8-carboxamideN-hydroxy-4-(2-methyl-2-(thiophen-2-yl)propanoyl)-2,3,4,5- +++tetrahydrobenzo[f][1,4]oxazepine-8-carboxamideN-hydroxy-4-(3-(4-methoxyphenyl)-2-phenylpropanoyl)-2,3,4,5- ++tetrahydrobenzo[f][1,4]oxazepine-8-carboxamideN-hydroxy-4-(2-(5-methyl-1H-tetrazol-1-yl)-2-phenylacetyl)- ++2,3,4,5-tetrahydrobenzo[f][1,4]oxazepine-8-carboxamideN-hydroxy-4-(2-phenyl-2-(1H-tetrazol-1-yl)acetyl)-2,3,4,5- ++tetrahydrobenzo[f][1,4]oxazepine-8-carboxamideN-hydroxy-4-(2-phenyl-2-((tetrahydro-2H-pyran-4-yl)oxy)acetyl)- +2,3,4,5-tetrahydrobenzo[f][1,4]oxazepine-8-carboxamideN-hydroxy-4-(2-hydroxy-3-methyl-2-phenylbutanoyl)-2,3,4,5- +tetrahydrobenzo[f][1,4]oxazepine-8-carboxamideN-hydroxy-4-(2-(4-hydroxypiperidin-1-yl)-2-phenylacetyl)-2,3,4,5- ++tetrahydrobenzo[f][1,4]oxazepine-8-carboxamideN-hydroxy-4-(2-phenyl-2-(2,2,2-trifluoroethoxy)acetyl)-2,3,4,5- ++tetrahydrobenzo[f][1,4]oxazepine-8-carboxamide4-(2-(tert-butoxy)-2-phenylacetyl)-N-hydroxy-2,3,4,5- ++tetrahydrobenzo[f][1,4]oxazepine-8-carboxamideN-hydroxy-4-(2-phenyl-2-(1H-pyrazol-1-yl)acetyl)-2,3,4,5- ++tetrahydrobenzo[f][1,4]oxazepine-8-carboxamideN-hydroxy-4-(2-methoxy-2-phenylpropanoyl)-2,3,4,5- ++tetrahydrobenzo[f][1,4]oxazepine-8-carboxamideN-hydroxy-4-(2-phenoxy-2-phenylacetyl)-2,3,4,5- ++tetrahydrobenzo[f][1,4]oxazepine-8-carboxamideN-hydroxy-4-(2-(2-oxopiperidin-1-yl)-2-phenylacetyl)-2,3,4,5- ++tetrahydrobenzo[f][1,4]oxazepine-8-carboxamideN-hydroxy-4-(2-methyl-2-phenylpropanoyl)-2,3,4,5- ++tetrahydrobenzo[f][1,4]oxazepine-8-carboxamideN-hydroxy-4-(2-(4-isobutoxyphenyl)-2-methylpropanoyl)-2,3,4,5- ++tetrahydrobenzo[f][1,4]oxazepine-8-carboxamide4-(1,1-dioxidotetrahydro-2H-thiopyran-4-carbonyl)-N-hydroxy- +++2,3,4,5-tetrahydrobenzo[f][1,4]oxazepine-8-carboxamideN-hydroxy-4-(4-methoxycyclohexane-1-carbonyl)-2,3,4,5- +++tetrahydrobenzo[f][1,4]oxazepine-8-carboxamideN-hydroxy-4-(1-(pyridin-2-yl)cyclopropane-1-carbonyl)-2,3,4,5- +++tetrahydrobenzo[f][1,4]oxazepine-8-carboxamideN-hydroxy-4-(4-phenyltetrahydro-2H-pyran-4-carbonyl)-2,3,4,5- ++tetrahydrobenzo[f][1,4]oxazepine-8-carboxamideN-hydroxy-4-(2-(pyridin-3-yl)propanoyl)-2,3,4,5- +++tetrahydrobenzo[f][1,4]oxazepine-8-carboxamideN-hydroxy-4-(4-methoxy-2-(pyridin-2-yl)butanoyl)-2,3,4,5- ++tetrahydrobenzo[f][1,4]oxazepine-8-carboxamide4-(3,3-difluorocyclopentane-1-carbonyl)-N-hydroxy-2,3,4,5- +++tetrahydrobenzo[f][1,4]oxazepine-8-carboxamideN-hydroxy-4-(1-methylcyclopropane-1-carbonyl)-2,3,4,5- +++tetrahydrobenzo[f][1,4]oxazepine-8-carboxamideN-hydroxy-4-(1-(methoxymethyl)cyclobutane-1-carbonyl)-2,3,4,5- +++tetrahydrobenzo[f][1,4]oxazepine-8-carboxamide4-(1-((1H-imidazol-1-yl)methyl)cyclopropane-1-carbonyl)-N- +++hydroxy-2,3,4,5-tetrahydrobenzo[f][1,4]oxazepine-8-carboxamideN-hydroxy-4-(1-(methoxymethyl)cyclopropane-1-carbonyl)-2,3,4,5- +++tetrahydrobenzo[f][1,4]oxazepine-8-carboxamideN-hydroxy-4-(2-methyl-3-phenylpropanoyl)-2,3,4,5- +++tetrahydrobenzo[f][1,4]oxazepine-8-carboxamide4-(1-acetylpyrrolidine-3-carbonyl)-N-hydroxy-2,3,4,5- ++tetrahydrobenzo[f][1,4]oxazepine-8-carboxamideN-hydroxy-4-(1-methylcyclopentane-1-carbonyl)-2,3,4,5- +++tetrahydrobenzo[f][1,4]oxazepine-8-carboxamideN-hydroxy-4-(1-(2-(trifluoromethyl)phenyl)cyclopropane-1- +++carbonyl)-2,3,4,5-tetrahydrobenzo[f][1,4]oxazepine-8-carboxamideN-hydroxy-4-(1-(3-(trifluoromethyl)phenyl)cyclopropane-1- +++carbonyl)-2,3,4,5-tetrahydrobenzo[f][1,4]oxazepine-8-carboxamideN-hydroxy-4-(tetrahydrofuran-3-carbonyl)-2,3,4,5- +++tetrahydrobenzo[f][1,4]oxazepine-8-carboxamideN-hydroxy-4-(1-(4-(trifluoromethyl)phenyl)cyclopropane-1- +++carbonyl)-2,3,4,5-tetrahydrobenzo[f][1,4]oxazepine-8-carboxamideN-hydroxy-4-(1-phenylcyclobutane-1-carbonyl)-2,3,4,5- +++tetrahydrobenzo[f][1,4]oxazepine-8-carboxamide4-(1-benzylcyclopropane-1-carbonyl)-N-hydroxy-2,3,4,5- +++tetrahydrobenzo[f][1,4]oxazepine-8-carboxamideN-hydroxy-4-(1-methoxycyclobutane-1-carbonyl)-2,3,4,5- +++tetrahydrobenzo[f][1,4]oxazepine-8-carboxamideN-hydroxy-4-(1-(phenylsulfonyl)cyclopropane-1-carbonyl)-2,3,4,5- +++tetrahydrobenzo[f][1,4]oxazepine-8-carboxamide4-(1-(4-fluorophenyl)cyclopropane-1-carbonyl)-N-hydroxy-2,3,4,5- +++tetrahydrobenzo[f][1,4]oxazepine-8-carboxamide4-(1-(4-chlorophenyl)cyclopropane-1-carbonyl)-N-hydroxy-2,3,4,5- +++tetrahydrobenzo[f][1,4]oxazepine-8-carboxamideN-hydroxy-4-(1-(4-methoxyphenyl)cyclopropane-1-carbonyl)- +++2,3,4,5-tetrahydrobenzo[f][1,4]oxazepine-8-carboxamide4-(1-(3-chlorophenyl)cyclopropane-1-carbonyl)-N-hydroxy-2,3,4,5- +++tetrahydrobenzo[f][1,4]oxazepine-8-carboxamide4-(1-(2-chlorophenyl)cyclopropane-1-carbonyl)-N-hydroxy-2,3,4,5- +++tetrahydrobenzo[f][1,4]oxazepine-8-carboxamideN-hydroxy-4-(1-(3-methoxyphenyl)cyclopropane-1-carbonyl)- +++2,3,4,5-tetrahydrobenzo[f][1,4]oxazepine-8-carboxamideN-hydroxy-4-(1-(pyridin-4-yl)cyclopropane-1-carbonyl)-2,3,4,5- +++tetrahydrobenzo[f][1,4]oxazepine-8-carboxamideN-hydroxy-4-(1-(pyrazin-2-yl)cyclopropane-1-carbonyl)-2,3,4,5- +++tetrahydrobenzo[f][1,4]oxazepine-8-carboxamideN-hydroxy-4-(1-phenoxycyclopropane-1-carbonyl)-2,3,4,5- ++tetrahydrobenzo[f][1,4]oxazepine-8-carboxamide4-(1-((1H-pyrazol-1-yl)methyl)cyclopropane-1-carbonyl)-N- +++hydroxy-2,3,4,5-tetrahydrobenzo[f][1,4]oxazepine-8-carboxamideN-hydroxy-4-(1-(thiophen-2-yl)cyclopropane-1-carbonyl)-2,3,4,5- +++tetrahydrobenzo[f][1,4]oxazepine-8-carboxamideN-hydroxy-4-(oxetane-3-carbonyl)-2,3,4,5- +++tetrahydrobenzo[f][1,4]oxazepine-8-carboxamideN-hydroxy-4-(3-methyloxetane-3-carbonyl)-2,3,4,5- +++tetrahydrobenzo[f][1,4]oxazepine-8-carboxamideN-hydroxy-8-(tetrahydro-2H-pyran-4-carbonyl)-6,7,8,9- ++tetrahydropyrazino[2,3-f][1,4]oxazepine-3-carboxamide8-(cyclohexanecarbonyl)-N-hydroxy-6,7,8,9-tetrahydropyrazino[2,3- +++f][1,4]oxazepine-3-carboxamide(R)-N-hydroxy-2-isopropyl-4-(tetrahydro-2H-pyran-4-carbonyl)- ++2,3,4,5-tetrahydrobenzo[f][1,4]oxazepine-8-carboxamide(R)-N-hydroxy-2-isopropyl-4-(1-methylcyclobutane-1-carbonyl)- ++2,3,4,5-tetrahydrobenzo[f][1,4]oxazepine-8-carboxamide(R)-4-formyl-N-hydroxy-2-isopropyl-2,3,4,5- ++tetrahydrobenzo[f][1,4]oxazepine-8-carboxamide(R)-N-hydroxy-2-(methoxymethyl)-4-(tetrahydro-2H-pyran-4- ++carbonyl)-2,3,4,5-tetrahydrobenzo[f][1,4]oxazepine-8-carboxamide(R)-N-hydroxy-2-(methoxymethyl)-4-(1-methylcyclobutane-1- ++carbonyl)-2,3,4,5-tetrahydrobenzo[f][1,4]oxazepine-8-carboxamide(R)-4-formyl-N-hydroxy-2-(methoxymethyl)-2,3,4,5- +++tetrahydrobenzo[f][1,4]oxazepine-8-carboxamide(S)-N-hydroxy-2-(methoxymethyl)-4-(tetrahydro-2H-pyran-4- ++carbonyl)-2,3,4,5-tetrahydrobenzo[f][1,4]oxazepine-8-carboxamide(S)-N-hydroxy-2-(methoxymethyl)-4-(1-methylcyclobutane-1- +++carbonyl)-2,3,4,5-tetrahydrobenzo[f][1,4]oxazepine-8-carboxamide(S)-4-formyl-N-hydroxy-2-(methoxymethyl)-2,3,4,5- ++tetrahydrobenzo[f][1,4]oxazepine-8-carboxamide(R)-N-hydroxy-2-phenyl-4-(tetrahydro-2H-pyran-4-carbonyl)- ++2,3,4,5-tetrahydrobenzo[f][1,4]oxazepine-8-carboxamide(R)-N-hydroxy-4-(1-methylcyclobutane-1-carbonyl)-2-phenyl- ++2,3,4,5-tetrahydrobenzo[f][1,4]oxazepine-8-carboxamide(R)-4-formyl-N-hydroxy-2-phenyl-2,3,4,5- +++tetrahydrobenzo[f][1,4]oxazepine-8-carboxamide(S)-N-hydroxy-2-phenyl-4-(tetrahydro-2H-pyran-4-carbonyl)- +++2,3,4,5-tetrahydrobenzo[f][1,4]oxazepine-8-carboxamide(S)-N-hydroxy-4-(1-methylcyclobutane-1-carbonyl)-2-phenyl- +++2,3,4,5-tetrahydrobenzo[f][1,4]oxazepine-8-carboxamide(S)-4-formyl-N-hydroxy-2-phenyl-2,3,4,5- +++tetrahydrobenzo[f][1,4]oxazepine-8-carboxamide(R)-N-hydroxy-4-(tetrahydro-2H-pyran-4-carbonyl)-3- +++(trifluoromethyl)-2,3,4,5-tetrahydrobenzo[f][1,4]oxazepine-8-carboxamide(R)-N-hydroxy-4-(oxetane-3-carbonyl)-3-(trifluoromethyl)-2,3,4,5- +++tetrahydrobenzo[f][1,4]oxazepine-8-carboxamideN-hydroxy-4-(tetrahydro-2H-pyran-4-carbonyl)-4,5-dihydro-2H- +++spiro[benzo[f][1,4]oxazepine-3,1′-cyclopropane]-8-carboxamide(S)-3-ethyl-N-hydroxy-4-(tetrahydro-2H-pyran-4-carbonyl)-2,3,4,5- +++tetrahydrobenzo[f][1,4]oxazepine-8-carboxamide(S)-N-hydroxy-3-isopropyl-4-(2-(tetrahydro-2H-pyran-4-yl)acetyl)- ++2,3,4,5-tetrahydrobenzo[f][1,4]oxazepine-8-carboxamide(S)-N-hydroxy-3-isopropyl-4-(tetrahydro-2H-pyran-4-carbonyl)- +++2,3,4,5-tetrahydrobenzo[f][1,4]oxazepine-8-carboxamide(S)-N-hydroxy-4-((1s,4R)-4-methoxycyclohexane-1-carbonyl)-3- +++methyl-2,3,4,5-tetrahydrobenzo[f][1,4]oxazepine-8-carboxamide(S)-N-hydroxy-4-((1r,4S)-4-methoxycyclohexane-1-carbonyl)-3- +++methyl-2,3,4,5-tetrahydrobenzo[f][1,4]oxazepine-8-carboxamide(S)-4-(1-formylpiperidine-4-carbonyl)-N-hydroxy-3-methyl-2,3,4,5- +++tetrahydrobenzo[f][1,4]oxazepine-8-carboxamide(S)-N-hydroxy-4-(3-(methoxymethyl)oxetane-3-carbonyl)-3-methyl- +++2,3,4,5-tetrahydrobenzo[f][1,4]oxazepine-8-carboxamide(S)-N-hydroxy-3-methyl-4-((R)-tetrahydro-2H-pyran-3-carbonyl)- +++2,3,4,5-tetrahydrobenzo[f][1,4]oxazepine-8-carboxamide(S)-N-hydroxy-3-methyl-4-((S)-tetrahydro-2H-pyran-3-carbonyl)- +++2,3,4,5-tetrahydrobenzo[f][1,4]oxazepine-8-carboxamide(S)-N-hydroxy-3-methyl-4-((R)-tetrahydrofuran-3-carbonyl)- +++2,3,4,5-tetrahydrobenzo[f][1,4]oxazepine-8-carboxamide(S)-N-hydroxy-3-methyl-4-((S)-tetrahydrofuran-3-carbonyl)-2,3,4,5- +++tetrahydrobenzo[f][1,4]oxazepine-8-carboxamide(S)-N-hydroxy-3-methyl-4-(2-(tetrahydro-2H-pyran-4-yl)acetyl)- ++2,3,4,5-tetrahydrobenzo[f][1,4]oxazepine-8-carboxamide(S)-N-hydroxy-4-(4-(methoxymethyl)tetrahydro-2H-pyran-4- +++carbonyl)-3-methyl-2,3,4,5-tetrahydrobenzo[f][1,4]oxazepine-8-carboxamide(S)-4-(3-ethyloxetane-3-carbonyl)-N-hydroxy-3-methyl-2,3,4,5- +++tetrahydrobenzo[f][1,4]oxazepine-8-carboxamide(S)-4-(3-(4-fluorophenoxy)propanoyl)-N-hydroxy-3-methyl-2,3,4,5- +++tetrahydrobenzo[f][1,4]oxazepine-8-carboxamide(S)-N-hydroxy-3-methyl-4-((1s,4R)-4- +++(trifluoromethoxy)cyclohexane-1-carbonyl)-2,3,4,5-tetrahydrobenzo[f][1,4]oxazepine-8-carboxamide(S)-N-hydroxy-3-methyl-4-((1r,4S)-4- +++(trifluoromethoxy)cyclohexane-1-carbonyl)-2,3,4,5-tetrahydrobenzo[f][1,4]oxazepine-8-carboxamide(S)-N-hydroxy-4-((1s,3R)-3-methoxycyclobutane-1-carbonyl)-3- +++methyl-2,3,4,5-tetrahydrobenzo[f][1,4]oxazepine-8-carboxamide(S)-N-hydroxy-4-((1r,3S)-3-methoxycyclobutane-1-carbonyl)-3- +++methyl-2,3,4,5-tetrahydrobenzo[f][1,4]oxazepine-8-carboxamide(S)-4-(3-(benzyloxy)cyclobutane-1-carbonyl)-N-hydroxy-3-methyl- +++2,3,4,5-tetrahydrobenzo[f][1,4]oxazepine-8-carboxamide(3S)-N-hydroxy-3-methyl-4-(2-(tetrahydrofuran-2-yl)acetyl)- +++2,3,4,5-tetrahydrobenzo[f][1,4]oxazepine-8-carboxamide(S)-4-(cyclohexanecarbonyl)-N-hydroxy-3-methyl-2,3,4,5- +++tetrahydrobenzo[f][1,4]oxazepine-8-carboxamide(S)-N-hydroxy-4-(3-methoxypropanoyl)-3-methyl-2,3,4,5- +++tetrahydrobenzo[f][1,4]oxazepine-8-carboxamide(S)-4-(4-fluorobenzoyl)-N-hydroxy-3-methyl-2,3,4,5- +++tetrahydrobenzo[f][1,4]oxazepine-8-carboxamide(S)-N-hydroxy-3-methyl-4-propionyl-2,3,4,5- +++tetrahydrobenzo[f][1,4]oxazepine-8-carboxamide(S)-4-(cyclopropanecarbonyl)-N-hydroxy-3-methyl-2,3,4,5- +++tetrahydrobenzo[f][1,4]oxazepine-8-carboxamide(S)-4-(cyclobutanecarbonyl)-N-hydroxy-3-methyl-2,3,4,5- +++tetrahydrobenzo[f][1,4]oxazepine-8-carboxamide(S)-4-(cyclopentanecarbonyl)-N-hydroxy-3-methyl-2,3,4,5- +++tetrahydrobenzo[f][1,4]oxazepine-8-carboxamide(S)-N-hydroxy-4-isobutyryl-3-methyl-2,3,4,5- +++tetrahydrobenzo[f][1,4]oxazepine-8-carboxamide(S)-N-hydroxy-4-(3-hydroxy-3-methylbutanoyl)-3-methyl-2,3,4,5- +++tetrahydrobenzo[f][1,4]oxazepine-8-carboxamide(S)-N-hydroxy-4-(3-hydroxy-2,2-dimethylpropanoyl)-3-methyl- +++2,3,4,5-tetrahydrobenzo[f][1,4]oxazepine-8-carboxamide(S)-N-hydroxy-4-(3-methoxy-3-methylbutanoyl)-3-methyl-2,3,4,5- +++tetrahydrobenzo[f][1,4]oxazepine-8-carboxamide(S)-4-(4-fluorotetrahydro-2H-pyran-4-carbonyl)-N-hydroxy-3- +++methyl-2,3,4,5-tetrahydrobenzo[f][1,4]oxazepine-8-carboxamide(3S)-N-hydroxy-3-methyl-4-(oxepane-4-carbonyl)-2,3,4,5- +++tetrahydrobenzo[f][1,4]oxazepine-8-carboxamide(S)-N-hydroxy-3-methyl-4-((S)-2-methyltetrahydro-2H-pyran-2- +++carbonyl)-2,3,4,5-tetrahydrobenzo[f][1,4]oxazepine-8-carboxamide(S)-N-hydroxy-3-methyl-4-((R)-2-methyltetrahydro-2H-pyran-2- ++carbonyl)-2,3,4,5-tetrahydrobenzo[f][1,4]oxazepine-8-carboxamide(3S)-N-hydroxy-4-(2-isopropyltetrahydrofuran-3-carbonyl)-3- +++methyl-2,3,4,5-tetrahydrobenzo[f][1,4]oxazepine-8-carboxamide(3S)-4-(5,5-dimethyltetrahydrofuran-2-carbonyl)-N-hydroxy-3- +++methyl-2,3,4,5-tetrahydrobenzo[f][1,4]oxazepine-8-carboxamide(3S)-N-hydroxy-3-methyl-4-(2-methyltetrahydrofuran-2-carbonyl)- +++2,3,4,5-tetrahydrobenzo[f][1,4]oxazepine-8-carboxamide(3S)-4-((2R)-7-oxabicyclo[2.2.1]heptane-2-carbonyl)-N-hydroxy-3- +++methyl-2,3,4,5-tetrahydrobenzo[f][1,4]oxazepine-8-carboxamide(3S)-4-((2S)-7-oxabicyclo[2.2.1]heptane-2-carbonyl)-N-hydroxy-3- +++methyl-2,3,4,5-tetrahydrobenzo[f][1,4]oxazepine-8-carboxamide(S)-N-hydroxy-4-(1-(methoxymethyl)cyclobutane-1-carbonyl)-3- +++methyl-2,3,4,5-tetrahydrobenzo[f][1,4]oxazepine-8-carboxamide(S)-N-hydroxy-3-methyl-4-(3-((tetrahydro-2H-pyran-4- ++yl)oxy)propanoyl)-2,3,4,5-tetrahydrobenzo[f][1,4]oxazepine-8-carboxamide(S)-N-hydroxy-4-(1-(methoxymethyl)cyclopropane-1-carbonyl)-3- +++methyl-2,3,4,5-tetrahydrobenzo[f][1,4]oxazepine-8-carboxamide(S)-N-hydroxy-3-methyl-4-((1r,3S)-3-phenoxycyclobutane-1- +++carbonyl)-2,3,4,5-tetrahydrobenzo[f][1,4]oxazepine-8-carboxamide(S)-N-hydroxy-3-methyl-4-((1s,3R)-3-phenoxycyclobutane-1- +++carbonyl)-2,3,4,5-tetrahydrobenzo[f][1,4]oxazepine-8-carboxamide(S)-N-hydroxy-3-methyl-4-((2R,3S)-2-methyltetrahydro-2H-pyran- +++3-carbonyl)-2,3,4,5-tetrahydrobenzo[f][1,4]oxazepine-8- carboxamide(S)-N-hydroxy-3-methyl-4-(3-(2,2,2-trifluoroethoxy)propanoyl)- +++2,3,4,5-tetrahydrobenzo[f][1,4]oxazepine-8-carboxamide(S)-N-hydroxy-4-((2S,4S)-2-isopropyltetrahydro-2H-pyran-4- +++carbonyl)-3-methyl-2,3,4,5-tetrahydrobenzo[f][1,4]oxazepine-8-carboxamide (S)-4-benzoyl-N-hydroxy-3-methyl-2,3,4,5- +++tetrahydrobenzo[f][1,4]oxazepine-8-carboxamide(S)-4-(2-(4-fluorophenyl)-2-methylpropanoyl)-N-hydroxy-3-methyl- +++2,3,4,5-tetrahydrobenzo[f][1,4]oxazepine-8-carboxamide(S)-4-(3-(4-fluorophenyl)-2,2-dimethylpropanoyl)-N-hydroxy-3- +++methyl-2,3,4,5-tetrahydrobenzo[f][1,4]oxazepine-8-carboxamide(S)-4-((S)-2,2-dimethyltetrahydro-2H-pyran-4-carbonyl)-N- +++hydroxy-3-methyl-2,3,4,5-tetrahydrobenzo[f][1,4]oxazepine-8- carboxamide(S)-4-((R)-2,2-dimethyltetrahydro-2H-pyran-4-carbonyl)-N- +++hydroxy-3-methyl-2,3,4,5-tetrahydrobenzo[f][1,4]oxazepine-8- carboxamide(R)-N-hydroxy-3-(methoxymethyl)-4-(tetrahydro-2H-pyran-4- +carbonyl)-2,3,4,5-tetrahydrobenzo[f][1,4]oxazepine-8-carboxamide(S)-N-hydroxy-3-(methoxymethyl)-4-(tetrahydro-2H-pyran-4- +++carbonyl)-2,3,4,5-tetrahydrobenzo[f][1,4]oxazepine-8-carboxamideN-hydroxy-4-(1-methoxycyclopropane-1-carbonyl)-2,3,4,5- +++tetrahydrobenzo[f][1,4]oxazepine-8-carboxamideN-hydroxy-4-(4-methyltetrahydro-2H-pyran-4-carbonyl)-2,3,4,5- +++tetrahydrobenzo[f][1,4]oxazepine-8-carboxamide4-(3-ethyloxetane-3-carbonyl)-N-hydroxy-2,3,4,5- +++tetrahydrobenzo[f][1,4]oxazepine-8-carboxamideN-hydroxy-4-(1-methyl-1H-pyrrole-2-carbonyl)-2,3,4,5- +++tetrahydrobenzo[f][1,4]oxazepine-8-carboxamideN-hydroxy-4-(1-methyl-1H-indole-2-carbonyl)-2,3,4,5- +++tetrahydrobenzo[f][1,4]oxazepine-8-carboxamide4-(2-(3,5-bis(trifluoromethyl)phenyl)acetyl)-N-hydroxy-2,3,4,5- ++tetrahydrobenzo[f][1,4]oxazepine-8-carboxamide4-(3,5-bis(trifluoromethyl)benzoyl)-N-hydroxy-2,3,4,5- ++tetrahydrobenzo[f][1,4]oxazepine-8-carboxamideN-hydroxy-4-(1-methyl-1H-pyrazole-3-carbonyl)-2,3,4,5- +++tetrahydrobenzo[f][1,4]oxazepine-8-carboxamideN-hydroxy-4-(2-mesitylacetyl)-2,3,4,5- +++tetrahydrobenzo[f][1,4]oxazepine-8-carboxamideN8-hydroxy-N2,N2-dimethyl-4-(tetrahydro-2H-pyran-4-carbonyl)- ++2,3,4,5-tetrahydrobenzo[f][1,4]oxazepine-2,8-dicarboxamide(R)-N-hydroxy-5-isopropyl-4-(tetrahydro-2H-pyran-4-carbonyl)- +2,3,4,5-tetrahydrobenzo[f][1,4]oxazepine-8-carboxamide(R)-N-hydroxy-5-isopropyl-4-(oxetane-3-carbonyl)-2,3,4,5- +tetrahydrobenzo[f][1,4]oxazepine-8-carboxamide(S)-N-hydroxy-5-isopropyl-4-(tetrahydro-2H-pyran-4-carbonyl)- +2,3,4,5-tetrahydrobenzo[f][1,4]oxazepine-8-carboxamide(S)-N-hydroxy-5-isopropyl-4-(oxetane-3-carbonyl)-2,3,4,5- +tetrahydrobenzo[f][1,4]oxazepine-8-carboxamide(R)-N-hydroxy-5-methyl-4-(1-methylcyclobutane-1-carbonyl)- +2,3,4,5-tetrahydrobenzo[f][1,4]oxazepine-8-carboxamide(R)-N-hydroxy-5-methyl-4-(tetrahydro-2H-pyran-4-carbonyl)- +2,3,4,5-tetrahydrobenzo[f][1,4]oxazepine-8-carboxamide(S)-N-hydroxy-5-methyl-4-(1-methylcyclobutane-1-carbonyl)- +++2,3,4,5-tetrahydrobenzo[f][1,4]oxazepine-8-carboxamide(S)-N-hydroxy-5-methyl-4-(tetrahydro-2H-pyran-4-carbonyl)- +++2,3,4,5-tetrahydrobenzo[f][1,4]oxazepine-8-carboxamide(S)-N-hydroxy-5-methyl-4-(4-methyltetrahydro-2H-pyran-4- +++carbonyl)-2,3,4,5-tetrahydrobenzo[f][1,4]oxazepine-8-carboxamide(S)-N-hydroxy-5-methyl-4-(3-methyloxetane-3-carbonyl)-2,3,4,5- +++tetrahydrobenzo[f][1,4]oxazepine-8-carboxamide(S)-N-hydroxy-5-methyl-4-(oxetane-3-carbonyl)-2,3,4,5- +++tetrahydrobenzo[f][1,4]oxazepine-8-carboxamide(S)-N-hydroxy-4-(3-(methoxymethyl)oxetane-3-carbonyl)-5-methyl- +++2,3,4,5-tetrahydrobenzo[f][1,4]oxazepine-8-carboxamide(S)-N-hydroxy-5-methyl-4-((S)-tetrahydro-2H-pyran-3-carbonyl)- +++2,3,4,5-tetrahydrobenzo[f][1,4]oxazepine-8-carboxamide(S)-N-hydroxy-5-methyl-4-((R)-tetrahydro-2H-pyran-3-carbonyl)- +++2,3,4,5-tetrahydrobenzo[f][1,4]oxazepine-8-carboxamide(S)-N-hydroxy-5-methyl-4-((S)-tetrahydrofuran-3-carbonyl)-2,3,4,5- +++tetrahydrobenzo[f][1,4]oxazepine-8-carboxamide(S)-N-hydroxy-5-methyl-4-((R)-tetrahydrofuran-3-carbonyl)- +++2,3,4,5-tetrahydrobenzo[f][1,4]oxazepine-8-carboxamide(S)-N-hydroxy-4-((1s,4R)-4-methoxycyclohexane-1-carbonyl)-5- +++methyl-2,3,4,5-tetrahydrobenzo[f][1,4]oxazepine-8-carboxamide(S)-N-hydroxy-4-((1r,4S)-4-methoxycyclohexane-1-carbonyl)-5- +++methyl-2,3,4,5-tetrahydrobenzo[f][1,4]oxazepine-8-carboxamide(S)-N-hydroxy-5-methyl-4-((R)-3-methyltetrahydrofuran-3- +++carbonyl)-2,3,4,5-tetrahydrobenzo[f][1,4]oxazepine-8-carboxamide(S)-N-hydroxy-5-methyl-4-((S)-3-methyltetrahydrofuran-3- +++carbonyl)-2,3,4,5-tetrahydrobenzo[f][1,4]oxazepine-8-carboxamide(S)-N-hydroxy-5-methyl-4-((R)-3-methyltetrahydro-2H-pyran-3- +++carbonyl)-2,3,4,5-tetrahydrobenzo[f][1,4]oxazepine-8-carboxamide(S)-N-hydroxy-5-methyl-4-((S)-3-methyltetrahydro-2H-pyran-3- +++carbonyl)-2,3,4,5-tetrahydrobenzo[f][1,4]oxazepine-8-carboxamide(S)-N-hydroxy-4-(4-(methoxymethyl)tetrahydro-2H-pyran-4- +++carbonyl)-5-methyl-2,3,4,5-tetrahydrobenzo[f][1,4]oxazepine-8-carboxamide(2R,5R)-N-hydroxy-4-(tetrahydro-2H-pyran-4-carbonyl)-2,3,4,5- ++tetrahydro-2,5-methanobenzo[f][1,4]oxazepine-8-carboxamide(2S,5S)-N-hydroxy-4-(tetrahydro-2H-pyran-4-carbonyl)-2,3,4,5- +tetrahydro-2,5-methanobenzo[f][1,4]oxazepine-8-carboxamide(S)-N-hydroxy-3-methyl-4-(2-methyl-2-(tetrahydro-2H-pyran-4- +++yl)propanoyl)-2,3,4,5-tetrahydrobenzo[f][1,4]oxazepine-8- carboxamide(S)-N-hydroxy-3-methyl-4-(2-methyl-2-(pyridin-3-yl)propanoyl)- +++2,3,4,5-tetrahydrobenzo[f][1,4]oxazepine-8-carboxamide(S)-4-(1H-benzo[d]imidazole-2-carbonyl)-N-hydroxy-3-methyl- +++2,3,4,5-tetrahydrobenzo[f][1,4]oxazepine-8-carboxamide(S)-N-hydroxy-3-methyl-4-((S)-tetrahydro-2H-pyran-2-carbonyl)- +++2,3,4,5-tetrahydrobenzo[f][1,4]oxazepine-8-carboxamide(S)-N-hydroxy-3-methyl-4-((R)-tetrahydro-2H-pyran-2-carbonyl)- +++2,3,4,5-tetrahydrobenzo[f][1,4]oxazepine-8-carboxamide(S)-N-hydroxy-3-methyl-4-((R)-3-methyltetrahydrofuran-3- +++carbonyl)-2,3,4,5-tetrahydrobenzo[f][1,4]oxazepine-8-carboxamide(S)-N-hydroxy-3-methyl-4-((S)-3-methyltetrahydrofuran-3- +++carbonyl)-2,3,4,5-tetrahydrobenzo[f][1,4]oxazepine-8-carboxamideN-hydroxy-4-(1-methylcyclobutane-1-carbonyl)-2-oxo-2,3,4,5- ++tetrahydro-1H-benzo[e][1,4]diazepine-7-carboxamide(S)-3-benzyl-N-hydroxy-4-(tetrahydro-2H-pyran-4-carbonyl)- +++2,3,4,5-tetrahydrobenzo[f][1,4]oxazepine-8-carboxamideN-hydroxy-4-(tetrahydro-2H-pyran-4-carbonyl)-3-(tetrahydro-2H- +pyran-4-yl)-2,3,4,5-tetrahydrobenzo[f][1,4]oxazepine-8- carboxamide

EQUIVALENTS

While the present disclosure has been described in conjunction with thespecific embodiments set forth above, many alternatives, modificationsand other variations thereof will be apparent to those of ordinary skillin the art. All such alternatives, modifications and variations areintended to fall within the spirit and scope of the present disclosure.

The invention claimed is:
 1. A compound of Formula I:

or a pharmaceutically acceptable salt thereof, wherein: X¹ is O; X² andX⁴ are each independently CR¹R², C═O, S(O) or SO₂; X³ is CR^(1′)R^(2′);Y¹ and Y⁴ are not bound to —C(O)NHOH and are each independently N orCR¹; Y² and Y³ are each independently N or CR¹ when not bonded to—C(O)NHOH and Y² and Y³ are C when bonded to —C(O)NHOH; L is selectedfrom the group consisting of —C(O)—, —C(O)(CR¹R²)_(m)—, and—C(O)(CR¹R²)_(m)O—, wherein L is bound to the ring nitrogen through thecarbonyl group; R is selected from the group consisting of —H, —C₁-C₆alkyl, —C₂-C₆ alkenyl, —C₄-C₈ cycloalkenyl, —C₂-C₆ alkynyl, —C₃-C₈cycloalkyl, —C₅-C₁₂ spirocycle, heterocyclyl, spiroheterocyclyl, aryl,and heteroaryl containing 1-5 heteroatoms selected from the groupconsisting of N, S, P, and O, wherein each alkyl, alkenyl, cycloalkenyl,alkynyl, cycloalkyl, spirocyclyl, heterocyclyl, spiroheterocyclyl, aryl,or heteroaryl is optionally substituted with one or more substituentsselected from the group consisting of —OH, halogen, oxo, —NO₂, —CN, —R¹,—R², —OR³, —NHR³, —NR³R⁴, —S(O)₂NR³R⁴, —S(O)₂R¹, —C(O)R¹, —CO₂R¹,—NR³S(O)₂R¹, —S(O)R¹, —S(O)NR³R⁴, —NR³S(O)R¹, heterocyclyl, aryl, andheteroaryl containing 1-5 heteroatoms selected from the group consistingof N, S, P, and O, with the proviso that R is not bound to L via anitrogen atom; R¹ and R² are independently, at each occurrence, selectedfrom the group consisting of —H, —R³, —R⁴, —C₁-C₆ alkyl, —C₂-C₆ alkenyl,—C₃-C₈ cycloalkenyl, —C₂-C₆ alkynyl, —C₃-C₈ cycloalkyl, heterocyclyl,aryl, heteroaryl containing 1-5 heteroatoms selected from the groupconsisting of N, S, P, and O, —OH, halogen, —NO₂, —CN, —NHC₁-C₆ alkyl,—N(C₁-C₆ alkyl)₂, —S(O)₂N(C₁-C₆ alkyl)₂, —N(C₁-C₆ alkyl)S(O)₂R⁵,—S(O)₂(C₁-C₆ alkyl), —(C₁-C₆ alkyl)S(O)₂R⁵, —C(O)C₁-C₆ alkyl, —CO₂C₁-C₆alkyl, —N(C₁-C₆ alkyl)S(O)₂C₁-C₆ alkyl, and —(CHR⁵)_(n)NR³R⁴, whereineach alkyl, alkenyl, cycloalkenyl, alkynyl, cycloalkyl, heterocyclyl,aryl, or heteroaryl is optionally substituted with one or moresubstituents selected from the group consisting of —OH, halogen, —NO₂,oxo, —CN, —R⁵, —OR³, —NHR³, —NR³R⁴, —S(O)₂N(R³)₂, —S(O)₂R⁵, —C(O)R⁵,—CO₂R⁵, —NR³S(O)₂R⁵, —S(O)R⁵, —S(O)NR³R⁴, —NR³S(O)R⁵, heterocyclyl,aryl, or heteroaryl containing 1-5 heteroatoms selected from the groupconsisting of N, S, P, and O; or R¹ and R² can combine with the carbonatom to which they are both attached to form a spirocycle,spiroheterocycle, or a spirocycloalkenyl; or R¹ and R², when onnon-adjacent atoms, can combine to form a bridging cycloalkyl orheterocycloalkyl; R^(1″) and R^(2′) are independently, at eachoccurrence, selected from the group consisting of —H, —C₁-C₆ alkyl,—C₂-C₆ alkenyl, —C₃-C₈ cycloalkenyl, —C₂-C₆ alkynyl, —C₃-C₈ cycloalkyl,heterocyclyl, —OH, halogen, —NO₂, —CN, —NHC₁-C₆ alkyl, —N(C₁-C₆ alkyl)₂,—S(O)₂N(C₁-C₆ alkyl)₂, —N(C₁-C₆ alkyl)S(O)₂R⁵, —S(O)₂(C₁-C₆ alkyl),—(C₁-C₆ alkyl)S(O)₂R⁵, —C(O)C₁-C₆ alkyl, —CO₂C₁-C₆ alkyl, —N(C₁-C₆alkyl)S(O)₂C₁-C₆ alkyl, and —(CHR⁵)_(n)NR³R⁴, wherein each alkyl,alkenyl, cycloalkenyl, alkynyl, cycloalkyl, or heterocyclyl isoptionally substituted with one or more substituents selected from thegroup consisting of —OH, halogen, —NO₂, oxo, —CN, —R⁵, —OR³, —NHR³,NR³R⁴, —S(O)₂N(R³)₂, —S(O)₂R⁵, —C(O)R⁵, —CO₂R⁵, —NR³S(O)₂R⁵, —S(O)R⁵,—S(O)NR³R⁴, —NR³S(O)R⁵, heterocyclyl, aryl, and heteroaryl containing1-5 heteroatoms selected from the group consisting of N, S, P, and O; orR^(1′) and R^(2′) can combine with the carbon atom to which they areboth attached to form a spirocycle, spiroheterocycle, or aspirocycloalkenyl; or R^(1′) and R^(2′) can combine with R¹ or R² onadjacent atoms to form a heterocycle, cycloalkyl, aryl, heteroarylcontaining 1-5 heteroatoms selected from the group consisting of N, S,P, and O, or cycloalkenyl; or R^(1″) and R^(2′) can combine with R¹ orR² on non-adjacent atoms, to form a bridging cycloalkyl orheterocycloalkyl; R³ and R⁴ are independently, at each occurrence,selected from the group consisting of —H, —C₁-C₆ alkyl, —C₂-C₆ alkenyl,—C₃-C₈ cycloalkenyl, —C₂-C₆ alkynyl, —C₃-C₈ cycloalkyl, heterocyclyl,aryl, heteroaryl containing 1-5 heteroatoms selected from the groupconsisting of N, S, P, and O, —S(O)₂N(C₁-C₆ alkyl)₂, —S(O)₂(C₁-C₆alkyl), —(C₁-C₆ alkyl)S(O)₂R⁵, —C(O)C₁-C₆ alkyl, —CO₂C₁-C₆ alkyl, and—(CHR⁵)_(n)N(C₁-C₆ alkyl)₂, wherein each alkyl, alkenyl, cycloalkenyl,alkynyl, cycloalkyl, heterocyclyl, aryl, and heteroaryl is optionallysubstituted with one or more substituents selected from the groupconsisting of —OH, halogen, —NO₂, oxo, —CN, —R⁵, —O(C₁-C₆alkyl),—NH(C₁-C₆ alkyl), N(C₁-C₆ alkyl)₂, —S(O)₂N(C₁-C₆ alkyl)₂, —S(O)₂NHC₁-C₆alkyl, —C(O)C₁-C₆ alkyl, —CO₂C₁-C₆ alkyl, —N(C₁-C₆ alkyl)S(O)₂C₁-C₆alkyl, —S(O)R⁵, —S(O)N(C₁-C₆ alkyl)₂, —N(C₁-C₆ alkyl)S(O)R⁵,heterocyclyl, aryl, and heteroaryl containing 1-5 heteroatoms selectedfrom the group consisting of N, S, P, and O; R⁵ is independently, ateach occurrence, selected from the group consisting of —H, —C₁-C₆ alkyl,—C₂-C₆ alkenyl, —C₃-C₈ cycloalkenyl, —C₂-C₆ alkynyl, —C₃-C₈ cycloalkyl,heterocyclyl, aryl, heteroaryl containing 1-5 heteroatoms selected fromthe group consisting of N, S, P, and O, —OH, halogen, —NO₂, —CN,—NH(C₁-C₆ alkyl), —N(C₁-C₆ alkyl)₂, —S(O)₂NH(C₁-C₆ alkyl), —S(O)₂N(C₁-C₆alkyl)₂, —S(O)₂C₁-C₆ alkyl, —C(O)C₁-C₆ alkyl, —CO₂C₁-C₆ alkyl, —N(C₁-C₆alkyl)SO₂C₁-C₆ alkyl, —S(O)(C₁-C₆ alkyl), —S(O)N(C₁-C₆ alkyl)₂, —N(C₁-C₆alkyl)S(O)(C₁-C₆ alkyl) and —(CH₂)_(n)N(C₁-C₆ alkyl)₂; n isindependently and at each occurrence an integer from 0 to 6; and m isindependently and at each occurrence an integer from 1 to
 6. 2. Thecompound of claim 1, wherein: X⁴ is CR¹R².
 3. The compound of claim 1,wherein the compound is of the Formula IA:

or a pharmaceutically acceptable salt thereof.
 4. The compound of claim3, wherein X⁴ is CR¹R².
 5. The compound of claim 1, wherein the compoundis of the Formula IB

or a pharmaceutically acceptable salt thereof.
 6. The compound of claim5, wherein X⁴ is CR¹R².
 7. A pharmaceutical composition comprising acompound of claim 1 and a pharmaceutically acceptable carrier.
 8. Thecompound of claim 4, wherein X² is CR¹R², wherein R¹ is —H, or —C₁-C₆alkyl; and R² is —H, —R³, aryl, or —C₁-C₆ alkyl optionally substitutedwith one or more substituents selected from oxo, —OR³, and —NR³R⁴. 9.The compound of claim 8, wherein X³ is CR^(1′)R^(2′), wherein R^(1′) is—H, or —C₁-C₆ alkyl; and R^(2′) is —H, heterocyclyl, or —C₁-C₆ alkyloptionally substituted with one or more substituents selected fromhalogen, aryl, and —OR³.
 10. The compound of claim 9, wherein Y¹ is CR¹,Y³ is CR¹, and Y⁴ is CR¹.
 11. The compound of claim 10, wherein L is—C(O)—.
 12. The compound of claim 6, wherein X² is CR¹R²; R¹ is —H, or—C₁-C₆ alkyl; and R² is —H, —R³, aryl, or —C₁-C₆ alkyl optionallysubstituted with one or more substituents selected from oxo, —OR³, and—NR³R⁴.
 13. The compound of claim 12, wherein X³ is CR^(1′)R^(2′),wherein R^(1′) is —H, or —C₁-C₆ alkyl; and R^(2′) is —H, heterocyclyl,or —C₁-C₆ alkyl optionally substituted with one or more substituentsselected from halogen, aryl, and —OR³.
 14. The compound of claim 13,wherein Y¹ is CR¹, Y² is CR¹, and Y⁴ is CR¹.
 15. The compound of claim14, wherein L is —C(O)—.
 16. The compound of claim 1, wherein thecompound isN-hydroxy-4-(3-methoxy-2,2-dimethylpropanoyl)-2,3,4,5-tetrahydrobenzo[f][1,4]oxazepine-8-carboxamide,or a pharmaceutically acceptable salt thereof.
 17. The compound of claim1, wherein the compound is(S)-4-(1-acetylpiperidine-4-carbonyl)-N-hydroxy-3-methyl-2,3,4,5-tetrahydrobenzo[f][1,4]oxazepine-8-carboxamide,or a pharmaceutically acceptable salt thereof.
 18. The compound of claim1, wherein the compound is(S)—N-hydroxy-5-methyl-4-((S)-3-methyltetrahydro-2H-pyran-3-carbonyl)-2,3,4,5-tetrahydrobenzo[f][1,4]oxazepine-8-carboxamide,or a pharmaceutically acceptable salt thereof.
 19. The compound of claim1, wherein the compound(S)-6-fluoro-N-hydroxy-3-methyl-4-(4-methyltetrahydro-2H-pyran-4-carbonyl)-2,3,4,5-tetrahydrobenzo[f][1,4]oxazepine-8-carboxamide,or a pharmaceutically acceptable salt thereof.
 20. A pharmaceuticalcomposition comprising a compound of claim 16 and a pharmaceuticallyacceptable carrier.
 21. A pharmaceutical composition comprising acompound of claim 17 and a pharmaceutically acceptable carrier.
 22. Apharmaceutical composition comprising a compound of claim 18 and apharmaceutically acceptable carrier.
 23. A pharmaceutical compositioncomprising a compound of claim 19 and a pharmaceutically acceptablecarrier.